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Pathology - Research and Practice
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PATHOLOGY RESEARCH PRACTICE
Review
The potential role of miRNAs in the pathogenesis of adrenocortical carcinoma - A focus on signaling pathways interplay
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Heba M. Midana, Gouda Kamel Helal b,c, Ahmed I. Abulsoud d,e,*,1, Shereen Saeid Elshaer e, f, Ahmed A. El-Husseiny d,8, Doaa Fathi e, Nourhan M. Abdelmaksoude, Sherif S. Abdel Mageedh, Mohammed S. Elballal ª, Mohamed Bakr Zaki1, Mai A. Abd-Elmawla3, Tohada M. AL-Noshokatye, Nehal I. Rizk , Mahmoud A. Elrebehy ª, Walaa A. El-Dakrouryk, Amr H. Hashem , Ahmed S. Doghish a, d, ** , 2
a Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt b Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo 11231, Egypt
” Department of Pharmacology and Toxicology, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
d Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
e Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt Department of Biochemistry, Faculty of Pharmacy (Girls), Al-Azhar University, Nasr City, Cairo 11823, Egypt % Department of Biochemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City 11829, Cairo, Egypt
h Pharmacology and Toxicology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt Biochemistry, Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Menoufia 32897, Egypt Biochemistry, Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt
k Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt Botany and Microbiology Department, Faculty of Science, Al-Azhar University, Nasr City 11884, Cairo, Egypt
Abbreviations: ACC, Adrenocortical carcinoma; Ago, Argonaute1; AIMAH, ACTH-independent macronodular adrenal hyperplasia; AKT, Protein kinase B; AMO, Anti-miRNA oligonucleotide; APC, Adenomatous Polyposis Coli; AREG, Amphiregulin; AuNP, Gold nanoparticle; Bax, BCL2 associated X; Bcl-2, B-cell lymphoma 2; BIRC5, Baculoviral IAP Repeat Containing 5; cAMP, Cyclic adenosine monophosphate; CDK1, Cyclin-dependent kinase 1; CDKN1A, Cyclin-dependent kinase inhibitor 1 A; CI, The Combination Index; c-Met, Mesenchymal-epithelial transition factor; CYP11B2, Cytochrome P450 family 11 subfamily B member 2; DGCR8, DiGeorge Critical Region 8; DICER, An endoribonuclease enzyme that in humans is encoded by the DICER1 gene; DKK1, Dickkopf-Related Protein 1; DNA, Deoxyribonucleic Acid; B DNMT3A, DNA (cytosine-5)-Methyltransferase 3 A; Drosha, Double-stranded RNA-specific endoribonuclease; E, Etoposide; E2F3, E2 F Transcription factor 3; EGFR, The Epidermal Growth Factor Receptor; EMT, Epithelial-mesenchymal transition; ERK, Extracellular signal-regulated kinase; FASN, Fatty acid synthase; FITC, Fluorescein isothiocyanate; Fzd, Frizzled; Gli3, GLI family zinc finger 3; GRB2, Growth factor receptor-bound protein 2; GSK3, Glycogen synthase kinase 3; HDL, high-density lipoprotein; hMC2R, Human melanocortin receptor 2; HMGA2, High mobility group A2; IGF2, Insulin-Like Growth Factor 2; IGFR1/ IGF-IR, Insulin-like growth factor 1 receptor; IRAK1, Interleukin-1 Receptor-Associated Kinase 1; JAK, The Janus Kinase; KRAS, Kristen rat sarcoma viral oncogene homolog; LRP6, Low Density Lipoprotein Receptor-Related Protein 6; M, Mitotane; MAPK, Mitogen-activated protein kinase; MATR3, MicroRNAs, Matrin 3MiRNAs/miR; MMAD, Massive macronodular adrenocortical disease; mRNA, Messenger RNA; MTDH, Metadherin; mTOR, Mammalian target of rapamycin; nab-paclitaxel, Nanoparticle albumin- bound form of the antimicrotubular medication paclitaxel; ncRNAs, Non-coding RNAs; Notch 1, Neurogenic locus notch homolog protein 1; P, Cisplatin; PCDC4, Programmed cell death protein 4; PI3K, The activated phosphoinositide-3-kinase; PKA, Protein kinase; PPNAD, Primary pigmented nodular adrenocortical disease; pre-miRNA, Precursor miRNA; pri-miRNA, Primary miRNA; PTEN, Phosphatase and tensin homolog; PUMA, P53 upregulated modulator of apoptosis; Raf1, Proto- oncogene serine/threonine kinase; Ran, RAS-related Nuclear protein; RISC, RNA-induced silencing complex; RNA Pol II, RNA polymerase II; RT-PCR, Real-time polymerase chain reaction; SF1, Steroidogenic factor-1; sHDL, synthetic-HDL nanoparticles; Shh, Sonic Hedgehog; SOCS, Suppressor of Cytokine Signaling; SPARC, Secreted protein acidic rich in cysteine; STAT, Signal Transducer and Activator of Transcription; SUFU, Suppressor of fused homolog; TRAF6, TNF Receptor- Associated Factor 6; TRBP/ TARBP2, Transactivation response element RNA-binding protein; UTR, Untranslated region; WISP2, WNT1-inducible-signaling pathway protein 2; Wnt, wingless-related integration site; ZEB1, Zinc finger E-box binding homeobox 1.
* Corresponding author at: Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt.
** Corresponding author at: Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt. E-mail addresses: abulsoudahmed@azhar.edu.eg (A.I. Abulsoud), ahmed_doghish@azhar.edu.eg (A.S. Doghish).
1 https://orcid.org/0000-0002-7876-3425
2 https://orcid.org/0000-0002-0136-7096
https://doi.org/10.1016/j.prp.2023.154690
ARTICLE INFO
Keywords:
MiRNA Adrenocortical carcinoma ACC Therapeutic intervention Pathogenesis Biomarker
ABSTRACT
Adrenocortical carcinoma (ACC) is a highly malignant infrequent tumor with a dismal prognosis. microRNAs (miRNAs, miRs) are crucial in post-transcriptional gene expression regulation. Due to their ability to regulate multiple gene networks, miRNAs are central to the hallmarks of cancer, including sustained proliferative signaling, evasion of growth suppressors, resistance to cell death, replicative immortality, induction/access to the vasculature, activation of invasion and metastasis, reprogramming of cellular metabolism, and avoidance of immune destruction. ACC represents a singular form of neoplasia associated with aberrations in the expression of evolutionarily conserved short, non-coding RNAs. Recently, the role of miRNAs in ACC has been examined extensively despite the disease’s rarity. Hence, the current review is a fast-intensive track elucidating the po- tential role of miRNAs in the pathogenesis of ACC besides their association with the survival of ACC.
1. Introduction
Adrenocortical cancer (ACC) is a highly aggressive malignancy of the endocrine system, occurring at a rate of 0.72-1.02 cases per million individuals per year. It is associated with a poor prognosis, as evidenced by a five-year survival rate of only 22% [1]. In southern Brazil, a study found a 10-15 times greater frequency in children [2]. Despite being rare, ACC has a poor prognosis; 20-50% of individuals are found to have advanced or metastatic disease, and overall survival (OS) is typically less than one year [3,4]. ACC has a bimodal age incidence, with peak years of occurrence in the first and fourth decades of life. The clinical course of childhood ACC is less aggressive, has a high incidence of virilization, notable overproduction of androgens, and may be more responsive to surgery and other therapy methods. ACC in adults, on the other hand, typically appears as a combined Cushing and virilizing syndrome, with overproduction of corticoids and androgens and a much more aggressive clinical course, resulting in rapid death within months or years [5]. Varied series of patients with ACC appear to have varied sex distribu- tions. The ratio of female to male patients with ACC was found to be 4:1 [5]. Few reports reported a male predominance [6-9]. The majority of articles stated there was no relationship between patient sex and sur- vival [9-11], whereas a few research claimed women had a higher survival rate [7,12]. There is currently minimal information available on racial and/or ethnic characteristics in ACC patients. According to several studies, white people with ACC tend to predominate more than black and Asian patients [13,14].
microRNAs (miRNAs, miRs) are small (18-22 nucleotide) non- coding RNAs (ncRNAs) that are considered essential components of the post-transcriptional regulatory network that governs gene expres- sion [15]. miRNAs, the endogenous mediators of RNA interference as components of the epigenetic machinery, regulate various fundamental cellular processes, and variations in their expression have been identi- fied in multiple diseases [16-19] including cancer [20-51], liver dis- eases [52], bone diseases [53], cardiovascular diseases [54,55], metabolic syndrome [56-58], rheumatoid arthritis [59,60], diabetes [61-64], and coronavirus disease 2019 (COVID-19) infection [65-68], and Alzheimer’s [69,70]. When miRNA expression is aberrant, it throws off the homeostatic balancing of proteins involved in the pathways that control cell division, proliferation, apoptosis, and resistance to chemo- therapy. Thus, oncogenic miRNA overexpression promotes carcinogen- esis, whereas tumor suppressor miRNA underexpression contributes to it. Furthermore, miRNA expression is tissue-specific, while the same miRNA can promote or inhibit tumor growth depending on the type of tissue it is expressed in.
miRNA can be oncogenic or tumor suppressive in distinct tissues [71]. Moreover, miRNAs have been revealed to be crucial for the adrenal gland’s physiological functioning and ACC’s initiation and progression. The expression of proteins linked to ACC is heavily regulated by miRNAs [72,73]. Understanding the tumor biology of ACC and the molecular pathways involved is a goal of the ongoing investigation into the role of miRNA regulation in this carcinogenesis. In this review, we aim to provide a concise summary of the most recent findings on the potential
involvement of miRNAs in ACC pathogenesis and survival, with an emphasis on the interplay between signaling pathways.
An online search was conducted between January and April of 2023 using the terms “adrenocortical carcinoma” (or “ACC”), “microRNAs” (or “miRNAs”), “Signaling pathway,” and “pathogenesis” in order to locate research publications and reviews that had been written in English over the course of the previous ten years. They were discovered by searching several medical databases, such as ScienceDirect and PubMed, among others. The most consideration was given to the reviews as well as the original articles.
2. miRNAs biogenic pathways and function
2.1. miRNAs biogenic pathways
miRNAs and other ncRNAs regulate gene expression in every eukaryotic species. The complexity of the pathway that leads to miRNA production has recently been recognized, particularly in terms of its ability to adapt, the regulation it is subject to, and its interaction with other biological processes [74-79].
The mature form of miRNA is the end product of the mechanism that leads to its production. It is produced when the Precursor miRNA (pre- miRNA) that Dicer is processing is cleaved into its functional form. Exportin 5 is responsible for transporting the pre-miRNA to the cyto- plasmic partition, where the microprocessor complex then processes it to convert it to the Primary miRNA (pri-miRNA) form. RNA polymerase II is the primary enzyme that is responsible for the transformation of miRNA genes into pri-miRNA. This transformation occurs when the miRNA gene is transcribed into the pri-miRNA (Fig. 1) [80-83]. The previous steps show how miRNAs are biogenically produced in the ca- nonical pathway.
Recent evidence suggests that specific miRNAs may follow non- canonical processing pathways, deviating from the traditional bio- geny. The following generic categories may be utilized in dividing non- canonical miRNA production routes: Drosha independent and Dicer in- dependent [84-86].
2.2. Function of miRNAs
Evidence suggests that a malfunction in the regulation of the pro- cessing of ncRNAs is one factor contributing to the development of cancers [87-89]. Mainly miRNA mutations are linked to the develop- ment of cancer. miRNAs are essential in controlling mitochondrial genes and proteins, thereby boosting or suppressing metabolic reprogramming and, as a result, the initiation and spread of cancer [90]. Alterations in miRNA expression are associated with cancer in several ways, including chromosomal rearrangements, epigenetic processes, transcriptional dysregulation, chemical alterations and editing, and protein abnormal- ities. It appears that the RNA-induced silencing complex (RISC) can restrict the production of miRNA in several different ways. The removal of miRNAs from the translation machinery illustrates this type of pro- cess. Additional examples include targeting miRNA and inhibiting
translation [78,91,92].
However, miRNAs may be ineffectual in controlling gene expression if they cannot attach to any target ncRNAs. miRNAs were initially designed to regulate gene expression. We use a “miRNA sponging” technique to speed up this process. The use of synthetic miRNA sponges hastened the development of cancer in human cells by inhibiting miRNA function. Different miRNAs can regulate the same target, whereas a single one can affect many targets. Different miRNAs can be identified by their unique fingerprints [93-96]. Depending on the specific cellular expression patterns involved, it can either support or inhibit the for- mation of tumors. Additionally, it may encourage metabolic reprog- ramming, a characteristic of cancers, and the production of cancer stem cells [97-102].
3. Regulatory mechanisms of miRNAs in ACC
It has been reported that ACC is associated with the dysregulation of signaling pathways crucial for the organogenesis and regulation of the adrenal cortex [103]. Besides, miRNAs play a key role in the dysregu- lation of signaling pathways implicated in the pathophysiology of ad- renal gland cancer (Table 1) [104].
3.1. Wnt/ß-catenin signaling pathway
Adrenocortical growth and action depend on the Wnt (wingless- related integration site) signaling mechanism, which modulates cell development and differentiation [105,106]. The buildup of ß-catenin is triggered by the inactivation of glycogen synthase kinase 3 (GSK3) via the interaction of the Wnt ligand with the Frizzled (Fzd) receptor. Cell proliferation target genes are transcriptionally activated by the nuclear translocation of ß-catenin (Fig. 2) [107].
Interestingly, human malignancies have been associated with the activation of Wnt signaling and the consequent buildup of ß-catenin [108-110]. In primary pigmented nodular adrenocortical disease (PPNAD) and massive macronodular adrenocortical disease (MMAD), miRNAs are related to adrenal tumors by the Wnt signaling pathway. Compared to normal adrenal tissue, PPNAD was shown to have a sig- nificant down-regulation of miR-449 and a significant up-regulation of its target gene, WNT1-inducible-signaling pathway protein 2 (WISP2). It was shown that cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) promotes the Wnt pathway by inhibiting miR-449 in PPNAD cells since miR-449 expression was enhanced while WISP2 production dropped when PKA action was suppressed in PPNAD cells. Notably, Increased midnight cortisol concentrations were linked with decreased levels of let-7b and subsequently deteriorating disease severity [111].
Compared to normal adrenal tissue, ACTH-independent macro- nodular adrenal hyperplasia (AIMAH) tissue was reported to have altered expression levels of various miRNAs. In particular, miR-200b, which seems to block Matrin 3 (MATR3), a nuclear protein that con- trols transcription, was the most negatively regulated miRNA in AIMAH. Indeed, the evidence that PKA degrades MATR3 in healthy tissues raises the potential that AIMAH has another relationship to the cAMP/PKA signaling pathway and that miRNAs play an essential function in the development of adrenal tumors. Moreover, increased midnight cortisol concentrations were positively linked with miR-130a and miR-382 upregulation in AIMAH [112,113].
Tumor suppressor miR-375 is downregulated in ACC and aldosterone-producing adrenal adenomas. The Wnt/ ß-catenin pathway is regulated by miR-375 knockout to enhance cell cycling by suppressing metadherin (MTDH) upstream of mitogen-activated protein kinase (MAPK) [114,115]. Also, miR-431 is distinctly produced in
Cytoplasm
Mature miRNA
Target miRNA
RNA Pol II
miRNA cleavage
miRNA gene
RISC
Transcription
Unwind
AGO
DROSHA
pre-RISC
DGCR8
pri-miRNA
miRNA duplex
pre-miRNA
TRBP
DICER
EXP 5
Nucleus
| Signaling Pathway | miRNAs | Expression | `Target | Ref. |
|---|---|---|---|---|
| Wnt/ ß-catenin | miR-449 | ↓ | WISP2 | [111] |
| miR-200b | ↓ | MATR3 | [112] | |
| miR-375 | ↓ | MTDH | [115] | |
| miR-431 | ↓ | ZEB1 | [116] | |
| P53 | miR-205 | ↓ | Bcl-2 | [138] |
| miR-7 | ↓ | CDK1 | [139] | |
| miR-483-3p | ↑ | PUMA | [140] | |
| miR-21 | ↑ | PCDC4 | [142] | |
| PI3K/Akt/mTOR | miR-99a | ↓ | mTOR - IGFR1 | [134] |
| miR-100 | ↓ | mTOR - IGFR1 | [134] | |
| miR-9-5 P | - | PTEN | [135] | |
| Sonic Hedgehog | miR-107 | ↑ | SUFU - Gli3 | [149] |
| Notch IGF2 | miR-1225-3p | ↑ | Notch 1 | [145] |
| miR-497 | ↓ | IGF2 | [154] | |
| miR-34a | ↓ | E2F3 | [155] | |
| miR-Let-7b | ↓ | HMGA2 | [156] | |
| miR-483-5p | ↑ | IGF2 | [156] | |
| Wnt/Fzd | miR-34a | ↓ | LRP6 | [158] |
| miR-17/92 | ↑ | APC, DKK1 | [159] | |
| miR-27 | ↑ | APC | [160] | |
| miR-335 | ↓ | Fzd4, | [161] | |
| ß-catenin | ||||
| miR-195 | ↓ | Fzd7, | [162] | |
| ß-catenin | ||||
| JAKs/STATS | miR-21 | ↑ | SOCS3 | [118] |
| miR-146a | ↓ | IRAK1, TRAF6 | [120] | |
| miR-29 | ↓ | DNMT3A | [122] | |
| EGFR | miR-7 | ↓ | EGFR | [125] |
| miR-34a | ↓ | EGFR/AKT/ c-Met | [126] | |
| miR-497 | ↓ | AKT/ERK | [127] | |
| miR-335 | ↓ | AREG | [128] | |
| miR-9 | ↓ | Sch. | ||
| miR-133a | ↓ | GRB2 | ||
| miR-146a | ↓ | IRAK1 | [129] | |
| miR-205 | ↓ | AKT3 |
AKT: Protein kinase B; APC: Adenomatous Polyposis Coli; AREG: Amphiregulin; Bcl-2: B-cell lymphoma 2; CDK1: Cyclin-dependent kinase 1; DKK1: Dickkopf- Related Protein 1; DNMT3A: DNA (cytosine-5)-Methyltransferase 3A; E2F3: E2 F Transcription factor 3; EGFR: The Epidermal Growth Factor Receptor; ERK: Extracellular signal-regulated kinase; Fzd: Frizzled; Gli3: GLI family zinc finger 3; GRB2: Growth factor receptor-bound protein 2; HMGA2: High mobility group A2; IGF2: Insulin-Like Growth Factor 2; IGFR1: Insulin-like growth factor 1 re- ceptor; IRAK1: Interleukin-1 Receptor-Associated Kinase 1; LRP6: Low Density Lipoprotein Receptor-Related Protein 6; MATR3: Matrin 3; MTDH: Metadherin; mTOR: Mammalian target of rapamycin; Notch 1: Neurogenic locus notch ho- molog protein 1; PCDC4: Programmed cell death protein 4; PTEN: Phosphatase and tensin homolog; PUMA: P53 upregulated modulator of apoptosis; SOCS: Suppressor of Cytokine Signaling; SUFU: Suppressor of fused homolog; TRAF: TNF Receptor-Associated Factor; WISP2: WNT1-inducible-signaling pathway protein 2; ZEB1: Zinc finger E-box binding homeobox 1.
chemo-sensitive cancer compared to chemo-resistant cancer in ACC and H295R cells. The lack of miR-431 regulation In ACC enables Zinc finger E-box binding homeobox 1 (ZEB1) to trigger Wnt, which increases B-catenin, enhancing the cell cycle [116].
3.2. JAK/STAT signaling pathway
The Janus kinase (JAK)/Signal transducer and activator of tran- scription (STAT) signaling pathway is a critical signaling pathway that regulates many cellular processes, including cell growth, differentiation, and survival. MiRNAs can regulate protein activity in the JAK/STAT pathway through various mechanisms [117]. One way miRNAs can regulate the JAK/STAT pathway is by directly targeting the mRNA of specific genes involved in the pathway. For example, miR-21 has been shown to directly target the mRNA of the negative regulator of JAK/- STAT pathway, suppressor of Cytokine Signaling 3 (SOCS3), leading to increased JAK/STAT signaling and cell proliferation (Fig. 2) [118].
Another way that miRNAs can regulate the JAK/STAT pathway is by
indirectly modulating the expression of genes involved in the pathway. For instance, miR-146a targets interleukin-1 receptor-associated kinase 1 (IRAK1) and TNF receptor-associated factor 6 (TRAF6), which are upstream regulators of the JAK/STAT pathway, indirectly leading to decreased JAK/STAT signaling and reduced cellular processes that are regulated by this pathway, such as cell proliferation and survival [119-121]. Similarly, miR-29 targets the mRNA of DNA (cytosine-5) — methyltransferase 3 A (DNMT3A), which negatively regulates the expression of SOCS1, another negative regulator of the JAK/STAT pathway (Fig. 2) [122].
Furthermore, miRNAs can regulate the activity of proteins that interact with the JAK/STAT pathway. For example, miR-155 has been shown to target the mRNA of the transcription factor PU1, which reg- ulates the expression of JAK/STAT target genes [123]. Overall, miRNAs can modulate the activity of proteins involved in the JAK/STAT signaling pathway by directly or indirectly targeting mRNA of specific genes, targeting upstream regulators of the pathway, or modulating the expression of negative regulators of the pathway.
3.3. EGFR signaling pathways
The epidermal growth factor receptor (EGFR) signaling pathway is a critical pathway that regulates cell proliferation, differentiation, and survival. Dysregulation of this pathway is often observed in cancer, including ACC. miRNAs have emerged as key regulators of the EGFR signaling pathway in ACC [124]. miRNAs can regulate the activity of proteins involved in the EGFR signaling pathway in several ways. For example, miR-7 has been shown to downregulate EGFR expression in ACC cells, inhibiting cell proliferation and migration. miR-7 targets the 3’ untranslated region (UTR) of EGFR mRNA, leading to its degradation and subsequent downregulation of EGFR protein levels [125].
miR-34a is another miRNA shown to regulate the EGFR signaling pathway in ACC. It targets several pathway components, including EGFR, AKT, and mesenchymal-epithelial transition factor (c-Met), inhibiting tumor growth and invasion (Fig. 2) [126].
miR-497 targets EGFR and inhibits cell proliferation and migration in ACC cells by downregulating EGFR expression. These miRNAs regu- late the EGFR pathway by targeting different components of the pathway, including EGFR itself, as well as downstream effectors such as AKT and extracellular signal-regulated kinase (ERK). Understanding the complex interplay between these miRNAs and the EGFR pathway may provide insights into developing novel therapeutic strategies for ACC (Fig. 2) [127]. Some miRNAs inhibit EGFR signaling in ACC cells by targeting the mRNA of the EGFR ligands as miR-335, which targets amphiregulin (AREG). At the same time, others can target EGFR adaptor proteins, such as miR-9 and miR-133a, by interacting with Shc and growth factor receptor-bound protein 2 (GRB2), respectively (Fig. 2) [128].
In addition to directly targeting EGFR and other components of the pathway, miRNAs can also indirectly regulate the EGFR pathway by targeting upstream regulators or downstream effectors. For example, miR-146a targets IRAK1, an upstream regulator of the EGFR pathway, inhibiting EGFR signaling. MiR-205 targets the downstream effector, AKT3, inhibiting the EGFR pathway and decreasing cell proliferation [129]. Overall, miRNAs play a critical role in regulating the activity of proteins involved in the EGFR signaling pathway in ACC. Understanding how miRNAs regulate this pathway may provide insights into devel- oping novel therapeutic strategies for this aggressive cancer.
3.4. PI3K/Akt/mTOR axis
The PI3K/Akt/ mammalian target of rapamycin (mTOR) signaling pathway plays an important role in the emergence of ACC. The activated phosphoinositide-3-kinase (PI3K) mediates protein kinase B (Akt) phosphorylation and consequently induces cellular proliferation and differentiation [130-132]. Besides, phosphatase and tensin homolog
miR-17
miR-92
miR-34a
miR-335 miR-195
miR-7
miR-497
TLR IL1-R
ITTT
EGFR
Cytokine
Wnt
200
DKK1
LRP5/6
Frizzled
miR-133a
P
P
MyD88
miR-146a
JAK2
JAK 1
GRB2
P
P
p85
IRAK1/4
P
miR-21
SOS
p110
P
TRAF6
SOCS 3
Dishevelled
P
Ras
GDP
miR-27
Ras
GTP
PI3K
A20
TAB2/3
STAT3
STAT3
SOCS
TAK1
miR-29
NEMO
DNMT3A
GSK-3B
CKla
Raf
P
PDK1
CYLD
IKKa
IKKB
P
P
miR-335 miR-195
Axin
miR-92
miR-17
STAT3
STAT3
APC
ß-Catenin
MEK
P
AKT
miR-34a
STAT3
B-Catenin
ERK
P
P
P
STAT3
miR-497
miR-205
SOCS 1
Cell growth + survival Angiogenesis Migration/invasion
NF-KB
P
SOCS 3
STAT3
ß-Catenin
Proliferation Invasion
Target genes
STAT3
TCF/LEF
P
(PTEN) is a dual-specific phosphatase that represses the PI3K/Akt signaling mechanism.
The reduced expression of miR-99a and miR-100 enhances cell proliferation by modulating PI3K/Akt signaling mechanism [133,134]. In pediatric ACC tissue samples, miR-99a and miR-100 were found to be downregulated in comparison to normal adrenal cancer, and their expression was negatively linked with both mTOR and insulin-like growth factor 1 receptor (IGFR1) mRNA [134]. Interestingly, the study by Qi et al. revealed that miR-9-5p increases apoptosis by modulating the PTEN/PI3K/Akt mechanism in the tissues of the piglet adrenal gland [135,136].
3.5. P53 signaling pathway
The transcription factor p53, which TP53 encodes, is essential for cells’ ability to prevent cancer growth. P53 is induced in response to the destruction of DNA and cellular stress signals, prompting DNA repair or apoptosis/senescence when destruction is irreversible [137].
The tumor suppressors miR-205 and miR-7 and the upregulated oncogenic miR-483-3p control p53’s downstream targets. Together, the reduction of miR-205-regulated B-cell lymphoma 2 (Bcl-2) repression of BCL2-associated X (Bax) and the reduction of miR-483-3p-induced p53 upregulated modulator of apoptosis (PUMA) production reduce p53- mediated apoptosis [138-141]. PUMA is a direct p53 downstream target that inhibits Bcl-2, triggering apoptosis [140]. Notably, it is well established that P53 causes cyclin-dependent kinase 1 (CDK1) tran- scriptional activity to be downregulated, causing G2 cell cycle arrest. The lack of miR-7 targeted repression causes CDK1 to become consti- tutively active, which overrides the p53-mediated G2 arrest and causes unregulated proliferation [139].
In vitro experiments by Romero et al. revealed that miR-21 down- regulation inhibits ACC growth and proliferation by upregulating the expression of programmed cell death protein 4 (PCDC4). PCDC4 is regar- ded as a suppressor of p53 expression [142].
3.6. Mutation of KRAS
Both benign and malignant cancers of diverse histological types and at distinct anatomic locations can have Kristen rat sarcoma viral onco- gene homolog (KRAS) mutations. Notably, mutations of KRAS induce common biological pathways that promote adrenal cancer survival, development, and immune surveillance. Oncogenic KRAS mutations function in part by modifying the activity of the miRNA regulatory pathways [143].
3.7. Notch signaling pathway
The Neurogenic locus notch homolog protein (Notch) signaling system significantly impacts the apoptosis, growth, and spread of tu- mors. Notch signaling can function as an oncogene or a tumor sup- pressor in various cancers. Moreover, Notch signaling can promote cancer by collaborating with other signaling systems by inhibiting dif- ferentiation. For instance, the upregulation of miR-1225-3p in recurring adrenal pheochromocytoma suppresses Notch-1 signaling [144,145].
3.8. Hedgehog signaling pathway
A glycoprotein ligand Sonic Hedgehog (Shh), its signaling pathway is believed to play a significant role in organogenesis [146]. It has been demonstrated to have significant paracrine effects on the growth and regeneration of the adrenal cortex [147]. Since Shh and steroidogenic factor-1 (SF1), key modulators of adrenocortical growth and activity, are co-expressed, cells expressing Shh seem able to produce steroid hormones. However, they lack the enzymes to produce glucocorticoid or mineralocorticoid hormones, preventing them from operating properly differentiated cells [148].
The fused homolog (SUFU) and GLI family zinc finger 3 (Gli3) sup- pressor represses the Shh signaling pathway. Indeed, miR-107 is upre- gulated in various cancers, including ACC [149]. The upregulation of
miR-107 in human endometrial cancer RL95-2 cells suppresses the production of SUFU and Gli3 and consequently induces Shh signaling-mediated cellular growth and proliferation [150]. Table 1 and Fig. 3 show the interplay between miRNAs and signaling pathways in the pathogenesis and treatment of ACC.
3.9. Insulin-like growth factor 2 (IGF2)
Insulin-like growth factor 2 (IGF2) is a protein that plays an impor- tant role in the growth and development of many tissues in the body, including the adrenal glands. IGF2 is overexpressed in many cases of ACC, and this is thought to contribute to the development and pro- gression of ACC by promoting cell growth, inhibiting cell death, and stimulating the formation of new blood vessels [151]. In addition, mu- tations in the IGF2 gene have been identified in some cases of ACC. These mutations can produce a faulty form of IGF2 that is more active than normal, further contributing to the growth and spread of cancer cells [152].
miRNAs are short RNA molecules that play a key role in regulating gene expression by binding to mRNA and inhibiting its translation into protein. miRNAs can regulate the activity of proteins involved in the IGF2 signaling pathway through different mechanisms [153]. One way miRNAs can modulate IGF2 signaling is by directly targeting the mRNA of specific genes involved in the pathway. For example, miR-497 has been shown to target the IGF2 mRNA directly, decreasing IGF2 protein levels and downstream signaling [154].
Another way that miRNAs can regulate IGF2 signaling is by indi- rectly targeting proteins involved in the pathway. For example, miR-34a has been shown to inhibit the expression of the transcription factor E2 F Transcription factor 3 (E2F3), which regulates IGF2 expression. By inhibiting E2F3, miR-34a indirectly downregulates IGF2 expression and signaling [155].
Additionally, miRNAs can regulate IGF2 signaling by targeting other proteins that modulate the pathway’s activity. For example, miR-let-7b has been shown to target the oncogene HMGA2, which regulates IGF2 signaling. By inhibiting HMGA2, miR-let-7b can indirectly decrease
miR-3-1225p
miR- 107
miR-431
Hedgehog
Sonic
miR-375
Notch 1
Wnt/ß- catenin
miR-99a
miR-200b
miRNA Targeting Pathways in ACC
PTEN/ miR-100 Akt/mTOR
miR-449
miR-5-9P
P53
miR-21
miR-205
miR-7
miR-3-483p
IGF2 expression and signaling [156]. miR-483-5p is a miRNA in the IGF2 gene and co-expressed with IGF2 in ACC. This miRNA has been shown to promote the growth of ACC cells by increasing the expression of IGF2 [156].
In summary, miRNAs can modulate IGF2 signaling in ACC by directly targeting IGF2 mRNA, indirectly regulating genes involved in IGF2 expression, and targeting other proteins involved in the pathway. These miRNA-mediated mechanisms can increase or decrease IGF2 signaling, depending on the specific miRNA and its target in the pathway. These findings suggest that miRNAs play an important role in regulating IGF2 expression in ACC and may represent a promising target for developing new therapies for this aggressive cancer.
3.10. Wnt/Fzd signaling pathway
The Wnt/Fzd signaling pathway has been implicated in the devel- opment and progression of ACC. This pathway is activated by the binding of Wnt ligands to Fzd receptors, leading to the stabilization and translocation of ß-catenin to the nucleus, which regulates the tran- scription of target genes. MiRNAs can regulate the activity of proteins involved in the Wnt/Fzd signaling pathway through various mecha- nisms [157].
One way miRNAs can regulate the Wnt/Fzd pathway is by targeting the mRNA of specific genes involved. For example, miR-34a has been shown to directly target the mRNA of the Wnt co-receptor low-density lipoprotein receptor-related protein 6 (LRP6), leading to decreased Wnt signaling [158].
Another way that miRNAs can regulate the Wnt/Fzd pathway is by indirectly modulating the expression of genes involved in the pathway. For instance, miR-17/92 cluster targets several negative regulators of the Wnt pathway, such as adenomatous polyposis coli (APC) and Dickkopf-related protein 1 (DKK1), leading to increased Wnt signaling [159]. Similarly, miR-27 has been shown to promote ACC cell prolifer- ation and invasion by targeting APC. MiR-27 overexpression leads to the stabilization of ß-catenin and activation of the Wnt pathway [160].
MiR-335 has been shown to inhibit ACC cell proliferation and in- vasion by targeting the Wnt signaling pathway. It targets several pathway components, including Fzd4 and ß-catenin, leading to the downregulation of Wnt signaling [161]. Similarly, miR-195 has been shown to inhibit ACC cell growth by targeting the Wnt pathway, spe- cifically Fzd7 and ß-catenin [162].
Overall, miRNAs have a complex and diverse role in regulating the Wnt/Fzd pathway in ACC, with some acting as inhibitors and others as activators. Understanding how miRNAs regulate this pathway in ACC may provide insights into developing novel therapeutic strategies for this aggressive cancer.
4. miRNAs and therapeutic intervention in ACC
ACC is an uncommon and heterogeneous cancer with unclear path- ogenesis and a bad prognosis. Till now, mitotane has been the mainstay intervention with etoposide, doxorubicin, and cisplatin. Potential drugs emerged, such as those targeting the insulin-like growth factor axis, tyrosine kinase inhibitors, radionuclide treatment, and immunotherapy [163,164]. Despite the wide range of therapies, ACC remains incurable, and treatment outcomes are disappointing. Many trials are done to improve the treatment protocol by exploring novel drugs. However, many challenges should be taken into consideration. For instance, the metabolism of the drugs by cytochrome P450 3A4 (CYP3A4) attenuates its efficiency and bioavailability. Another reason is the heterogeneity of the tumor, thus “one fits all” approach is unsuccessful. Additionally, a combination of drugs is needed to invade cancer effectively and to reduce drug resistance [165-168].
miRNAs-based therapeutic tools are one of the promising technolo- gies to restore normal cell functions that were interrupted due to ma- lignancy. The role of miRNAs in controlling cellular processes, their role
in carcinogenesis as oncogenes or tumor suppressor genes, and their aberrated regulation in cancer rationalize their utility in the therapeutic field. Interestingly, miRNA substitution by miRNA mimics and miRNA inhibition by anti-miRNA are practical approaches to utilize miRNAs in the therapeutic plan [169-172]. Indeed, miRNAs-based therapy pos- sesses several advantages over traditional chemotherapeutics, such as being natural molecules, having access all over body cells, and their ability to fine-tune biological pathways by targeting manifold genes leading to effective responses. However, these approaches are still in subclinical trials or phase II/III of clinical development. Crucially, these molecules may become the next-generation therapeutics for medical intervention [170,173,174].
4.1. Replacement of tumor suppressor miRNAs
miRNA replacement therapy is used to restore the normal function of endogenous tumor suppressor miRNAs. The main reasons for the decreased miRNA regulation in malignancies are genetic deletion of miRNA loci, epigenetic silencing via CpG island hypermethylation in the promoter region of miRNA genes, or decreased biogenesis and/or pro- cessing of miRNAs. Thus, reversing these processes using small mole- cules aids in restoring the global miRNA expression levels [175]. This is achieved using i) miRNA mimics: Small, chemically modified (2’-O-methoxy) RNA duplexes that can be loaded into RISC and achieve the downstream inhibition of the target mRNAs. ii) small-molecule en- hancers or expression vectors can express a specific type of miRNA [176]. These agents act at different stages of miRNA biogenesis, including processing, maturation, and strand selection [170].
Regarding ACC, the tumor suppressor miR-7 inhibits tumor growth and stimulates apoptosis at the G1 cell cycle in vitro. Glover et al. showed that administering systemic miR-7 in targeted, clinically safe delivery nanoparticles reduces ACC xenograft growth from both ACC cell lines and primary ACC cells. miR-7 targets proto-oncogene serine/threonine
kinase (Raf1) and mTOR and inhibits cyclin-dependent kinase 1 (CDK1) [141]. Moreover, miR-195 and miR-497 were reported to be down- regulated in ACC and accompanied by increased tumor growth and reduced apoptosis [140]. Caramuta et al. demonstrated that transfection of pre-miR-195 and pre-miR-497 in cell lines represses mRNA and pro- tein expression of TARBP2 and DICER, sequentially triggering apoptosis and lessening tumor growth (Fig. 4 and Table 2) [177].
Angiogenesis is a multi-step process that occurs when new blood vessels are created from preexisting ones. Their migration, tumor development, and endothelial cell differentiation are all triggered by tissue signals, including hypoxia [178-180]. Vascular endothelial growth factor (VEGF) promotes the creation of new blood vessels [181]. A tumor’s capacity to produce its own blood supply is essential to the tumor’s ability to develop. This stage of the development of cancers is crucial. Similarly to this, VEGFs are necessary for the emergence and growth of numerous different malignancies [182-185].
mTOR inhibitory agents promise therapeutic tools in cancers asso- ciated with stimulated Akt pathway and a relevant angiogenic compo- nent. This is attributed to the potential role of the mTOR signaling pathway in numerous transduction pathways needed for cell cycle development and cell proliferation. This pathway is stimulated in ACC, decreasing apoptosis and increasing cell proliferation. mTOR, raptor, and IGF-IR are direct targets for miR-99a/miR-100 inhibition in ACC. Synthetic miR-99a and miR-100 at different concentrations (5, 10, and 25 nmol/L) regress the expression of mTOR, raptor, and IGF-IR 3’-UTR sequences [134]. Consistently, Wu et al. reported the downregulated levels of miR-205 in ACC. miR-205 mimics induce apoptosis and impair cell proliferation by targeting the 3’UTR of Bcl-2 [138]. Worthy noted that the repression of Bcl-2 leads to cleaving Bax, releasing cytochrome c, caspase-9, and - 3, which are involved in the intrinsic apoptosis pathway [186].
In ACC cell lines H295R and SW13, low levels of the miR-486-3p were recorded, which is considered a key event in early ACC. In brief,
Wnt ß-catenin pathway
miR-203
Intrinsic Pathway
Wnt
IGF-1R
Chemicals, radiation & growth factor withdrawal
LRP
Frizzled
PIP2
PIP3
miR-99a miR-100
Pi3K
PTEN
miR-483-5p miR-139-5p
miR-205
Raf-1
BH3 only proteins
ZEB1
PDK1
BCL-2 BCL-XL MCL-1
miR-431
Dishevelled
miR-200c
miR-7
p53
MERK1/2
P
P
NDGR2/4
HMGA1
AKT
BAX BAK
Vimentin
GSK-3฿
CKla
BID
CDK
HMGA1
ERK1/2
miR-99a miR-100
Vimentin
miR-139-5p
Axin
APC
G1
TSC1/2
Steroid biogenesis
B-Catenin
C
C
C
Go
tBID
Migration
Invasion
M/G: Checkpoint
GDP
Rheb
GTP
Rheb
Caspase 9
C
M
Cell Cycle
Caspase 9
ß-Catenin
Gı/S Checkpoint
Apaf-1
mTORC1
Survivin
G2 /M
Checkpoint
Ub
G2
S
mTORC1
XIAP
SMAC
miR-149-3P
miR-7
Raptor
Deptor
mTOR
mLST8
B-Catenin
PRAS40
IAP antagonists
CIAPs
miR-335-5p
TCF/LEF
PDE2A
Cell Proliferation
Apoptosis
| miRNA | Deregulation in ACC | Therapeutic goal | Target genes | Outcome of intervention | Ref. |
|---|---|---|---|---|---|
| miR-7 | 11 | Replacement | RAF1, mTOR, CDK1 | Inhibit tumor growth and stimulate apoptosis at the G1 cell cycle | [141] |
| miR-195 | 44 | Replacement | DICER, TARBP2 | Inhibit tumor growth and stimulates apoptosis | [177] |
| miR-497 | |||||
| miR-99a miR-100 | 11 | Replacement | IGFR1, mTOR | Stimulate apoptosis and increase cell proliferation. | [134] |
| miR-205 | 11 | Replacement | BCL2, caspase-9 and - 3 | Induce apoptosis and impair cell proliferation | [138] |
| miR-486-3p | 11 | Replacement | FASN | Inhibit the lipid supply in cancer-proliferating cells | [187] |
| miR-335-5p | 11 | Replacement | Survivin | Inhibit apoptosis | [23] |
| miR-431 | 11 | Replacement | EMT-activator ZEB1 | Suppression of cell proliferation and stimulation of cell apoptosis | [191] |
| miR-193a-3p | 11 | Replacement | CYP11B2 | Aldosterone secretion induces G1-phase arrest and promotes apoptosis | [192] |
| miR-200c | 44 | Replacement | Vimentin | Inhibition of steroid production | [195] |
| miR-203 | 11 | Replacement | Wnt5a, ß-catenin | Inhibit cell proliferation and aldosterone production. | [198] |
| miR-24 | 11 | Replacement | 11ß-hydroxylase, Aldosterone | Control corticosteroid biosynthesis | [199, |
| miR-10b | synthase | 201] | |||
| miR-483-5p miR- | 11 | Inhibition | NDGR2, NDRG4 | Inhibit cell invasion by modulating epithelial-mesenchymal | [206] |
| 139-5p | transition | ||||
| miR-149-3p | tt | Inhibition | CDKN1A | Suppress cell viability | [210] |
| miR-139 | tt | Inhibition | PDE2A, Wnt, ß-catenin | Alleviate aggressiveness and better prognosis | [211] |
Bax: BCL2 associated X, apoptosis regulator, Bcl-2: B-cell lymphoma 2, CYP11B2 Cytochrome P450 family 11 subfamily B member 2, CDK1: Cyclin-dependent kinase 1, CDKN1A: Cyclin-dependent kinase inhibitor 1A, FASN: Fatty acid synthase, IGF-IR: Insulin-like growth factor-I receptor. mTOR: Mechanistic target of rapamycin, Raf1: Proto-oncogene serine/threonine kinase, ZEB1: Zinc finger E-box binding homeobox 1
the downregulated level of miR-486-3p results in an elevated fatty acid synthase (FASN) level, elevating the supply of lipids by increasing the de novo palmitate production. Notably, the lipid supply is an essential prerequisite for membrane biogenesis in cancer-proliferating cells as it confers the survival and growth of cancerous cells. miR-486-3p mimics suppress FASN levels, sequentially leading to depressed palmitate levels [187]. The lipogenic enzyme FASN exerts a metabolic-oncogenic func- tion and is a fundamental element in cancer hallmarks’ metabolic reprogramming. FASN-targeted drugs are recommended as future applicable drugs with optimized pharmacological properties and in vivo tolerability [188].
Subramanian et al. addressed that the miR-335 could be a potential therapeutic target in ACC. The miR335-5p was submitted as one of the tumor suppressor genes in ACC, and its inhibition is strongly associated with poor prognosis [73]. The miR335-5p mediates its function by targeting survivin, also known as baculoviral IAP repeat containing 5 (BIRC5), which is an inhibitor of apoptosis and upregulated in various cancer types, including ACC [189].
Additionally, regaining miR-431 via transfection with miR-431 mimics in H295R cells augments the cell responses to doxorubicin and mitotane. miR-431 mimics results in cell proliferation suppression and cell apoptosis stimulation via reversal of EMT-activator ZEB1, a crucial metastasis promoter [190,191]. Likewise, miR-193a-3p mimics injec- tion into H295R cells showed that the elevated miR-193a-3p expression inhibits cancer cell proliferation, and aldosterone secretion, induces G1-phase arrest, and promotes apoptosis through downregulation of its target gene, cytochrome P450 family 11 subfamily B member 2 (CYP11B2) [192]. CYP11B2 is elevated in ACC and triggers the secretion of aldosterone. Notably, CYP11B2 converts deoxycorticosterone to corticosterone, corticosterone to 18-hydroxycorticosterone, and 18-hydroxycorticosterone to aldosterone [193,194].
In parallel, Lu et al. declared that the potent testicular toxicant mono-butyl phthalate downregulates the tumor suppressor miR-200c, further elevating the vimentin level and steroidal hormone production [195]. Vimentin was reported as a bridge through which cholesterol mobilized from lipid droplets and transported to mitochondria to initiate steroid production [196,197]. Thus, artificial stimulation of miR-200c could attenuate vimentin levels and steroidogenesis. Relat- edly, another study revealed that restoration of the tumor-suppressing miRNA by miR-203 mimics showed declined cell proliferation and
aldosterone production via inhibiting the Wnt5a/B-catenin pathway (Fig. 4 and Table 2) [198].
Preceding literature has not been limited to studying the role of miRNAs in ACC etiopathogenesis but has also extended to studying the effect of miRNAs on steroidogenesis. Knockdown of Dicer 1 disrupted the regulation of genes involved in steroidogenesis. Furthermore, Rob- ertson et al. proposed that manipulating adrenal miRNAs is a novel valid therapeutic target in the clinical management of steroid hormone- related diseases via controlling steroid biosynthesis. One of these miR- NAs is miR-24, which suppresses the expression of the steroidogenic 116-hydroxylase and aldosterone synthase genes through direct binding [199]. 11ß-hydroxylase and aldosterone synthase are responsible for the terminal steps in synthesizing cortisol and aldosterone, respectively. Importantly, altered expression of these genes was observed in ACC [200]. Another is miR-10b, a hypoxia-inducible miRNA in ACC and a negative regulator of 11ß-hydroxylase and aldosterone synthase genes [201].
4.2. Abolishment of oncogenic miRNAs
Many miRNA antagonists inhibit the upregulated miRNAs involved in the pathological mechanisms and cease the normal function of the tumor-suppressive genes. miRNA inhibition therapy includes anti- miRNA oligonucleotide (AMO), modified AMOs [202], antagomirs [203], miRNA sponges [204], and miRNA masks [205].
In ACC, Agosta et al. reported that miR-483-5p and miR-139-5p inhibitors reduce ACC proliferation and tumor growth [206]. The miR-483-5p and miR-139-5p were markedly upregulated in ACC and stimulated aggressiveness by targeting N-myc downstream-regulated gene family members. Preceding studies reported that miR-483-5p and miR-139-5p accelerate invasion by modulating epithelial-mesenchymal transition (EMT) associated genes; thus, epithelial cells lose their polarity and convert into a mesenchymal phenotype [207]. miR-483-5p and miR-139-5p inhibitors mediate their action via increasing NDGR2 and NDRG4 proteins, respectively [206]. Notably, the NDGR family has pivotal roles in normal cell functions such as cell proliferation, differentiation, and stress responses. NDGR2 and NDGR4 are downregulated in ACC [208,209]. On the same side, Da Silva et al. study points to the miR-149-3p as a novel therapeutic target, where its induction promotes ACC cell viability by suppressing
cyclin-dependent kinase inhibitor 1 A (CDKN1A) [210]. Besides, Cris- tante et al. study reported that focusing on ß-Catenin opens novel ave- nues for therapeutic options in ACC. Stimulated Wnt/ß-Catenin axis elevates the expression of miR-139-5p and its host gene PDE2A which are implicated in ACC aggressiveness and bad prognosis (Fig. 4 and Table 2) [211,212].
The management of miRNA expression, either by mimicking or inhibiting them, is arising as a promising therapeutic tool. Nevertheless, miRNA-based therapeutics need to be improved by significant issues such as off-target effects, immunogenicity, and suitable delivery plat- forms. Recently, diverse techniques have been established to lessen off- target effects, reduce immunostimulation, and provide an efficient transfer to the target cells. Exogenous delivery vehicles are needed for successful translation to the clinic [213]. These systems should be se- lective for cancer cells; safe, as well as their pharmacokinetic profiles should be evaluated. Several delivery vehicles have been investigated, including polypeptides, adenovirus, and lipids; however, most of these systems have yet to be safe for human use. The deficiency of regulatory and safety guidelines has delayed the development of these products toward effective clinical translation [214]. Another challenge is the cost-benefit ratio, which is another restraint to the clinical utility of miRNA-based therapies compared with conventional drugs due to the high price of both miRNA biology products and nanocarriers [215,216].
5. Nanoparticles based therapy
ACC is associated with a bleak prognosis and presents a considerable clinical challenge due to delayed detection, elevated recurrence rates, and inadequate response to standard therapies. Utilizing suppressive tumor miRNAs as a therapeutic intervention is a promising approach, yet the effective delivery of these agents throughout the body remains a significant obstacle. Several miRNAs have been reported to exhibit reduced expression in ACC; however, their involvement in the patho- genesis of ACC remains unclear. It was reported that miR-7 could decrease cell proliferation in vitro and prompt G1 arrest of the cell cycle. The administration of miR-7 in a targeted delivery vesicular (EGFREDVTM nano cells) with clinical safety has been observed to reduce the growth of ACC xenografts originating from both ACC cell lines and primary ACC cells. miR-7 has been observed to target RAF1 and MTOR mechanistic target of rapamycin.
Furthermore, the administration of miR-7 treatment in an in vivo setting results in the suppression of cyclin-dependent kinase 1 (CDK1). CDK1 is observed to be overexpressed in ACC samples obtained from patients, while the expression of miR-7 exhibits an inverse correlation. In brief, the utilization of EDVTM nanoparticles for systemic delivery of miR-7 results in the inhibition of various oncogenic pathways and decreased ACC growth [217].
Gold nanoparticle (AuNP) conjugated with particular antibodies was formulated to target ACC cells selectively. This study employed immu- nohistochemistry to examine the purified polyclonal antibody raised against the 80-93, outer loop 1 position of the human melanocortin receptor 2 (hMC2R) using ACC and positive and negative control tissue micro-sections under light microscopy. Both the experimental and control commercial antibodies were observed to bind to cells that are recognized to express hMC2R selectively. The entities above were con- jugated with AuNPs labeled with Fluorescein isothiocyanate (FITC) and subsequently subjected to direct immunofluorescence analysis utilizing the H295R ACC cellular model. The probes exhibited a low background and exclusively identified cells that expressed hMC2R [218].
The administration of chemotherapeutic interventions for the treat- ment of ACC is associated with significant adverse effects. The growth of ACC cells and steroidogenesis rely heavily on cholesterol, with scav- enger receptor BI being overexpressed in ACC cells to facilitate choles- terol uptake from circulating high-density lipoprotein (HDL) cholesterol. It is postulated that synthetic-HDL nanoparticles (sHDL) devoid of cholesterol may reduce cholesterol levels and act in concert
with chemotherapeutic agents to produce superior anticancer outcomes with reduced drug dosages, thereby minimizing toxicity. The Cell-Titer Glo assay was employed to evaluate the antiproliferative effects of sHDL in combination with chemotherapeutic agents against ACC cells. The levels of cortisol were quantified from the cultivated media. The impact on steroidogenesis was assessed through real-time polymerase chain reaction (RT-PCR). The assessment of apoptosis induction was con- ducted through the utilization of flow cytometry.
The Combination Index (CI) analysis of sHDL in conjunction with etoposide (E), cisplatin (P), or mitotane (M) exhibited a synergistic effect in terms of antiproliferative activity. When used alone or in conjunction with chemotherapy medications, sHDL showed the ability to reduce cortisol production by 70-90% in comparison to controls. The results of the RT-PCR analysis demonstrated a significant decrease in the activity of steroidogenic enzymes for the group treated with sHDL compared to the group that did not receive sHDL. The application of combination therapy involving sHDL resulted in a significant increase in apoptosis by 30-50% compared to the administration of either drug or sHDL alone. A reduction in mitochondrial potential corroborated this. The combined use of sHDL can exhibit a synergistic effect and reduce the required dosage of M/E/P for achieving anticancer efficacy in ACC, partially attributed to the phenomenon of cholesterol starvation [219].
Gene expression profiling, a tool used in molecular technology, could provide new therapeutic targets for ACC. The albumin-binding matrix- associated protein SPARC (secreted protein acidic rich in cysteine) has been hypothesized as a reason for the enhanced efficacy of a nano- particle albumin-bound form of the antimicrotubular medication paclitaxel (nab-paclitaxel). Nineteen ACC tumors and four normal ad- renal glands were subjected to transcriptome profiling using Affymetrix U133 Plus2 expression microarrays to identify the genes that could serve as potential targets for therapeutic intervention. To determine the target proteins, the study conducted immunohistochemical analysis on 10 cases of adrenocortical carcinoma, 6 cases of benign adenomas, and 1 normal adrenal gland. Mitotane was evaluated against substances that inhibit specific targets in vitro, and mice xenograft using the 2 ACC cell lines H295R and SW-13. SPARC expression was elevated in ACC sam- ples. The in vitro inhibition of H295R and SW-13 cells by paclitaxel and nab-paclitaxel was observed at IC50 concentrations of 0.33 µM and 0.0078 µM for paclitaxel and 0.35 µM and 0.0087 µM for nab-paclitaxel, respectively. This is in comparison to mitotane concentrations of 15.9 µM and 46.4 µM. In vivo, therapy with nab-paclitaxel reduces tumor mass in both xenograft models compared to mitotane [220-223].
6. Conclusion
A variety of research supports the pathogenic importance of miRNAs in ACC. There are notable differences in the expression of miRNAs that may impact various ACC pathogenic pathways. However, there are still many discrepancies to be explained in the published miRNA profiles of ACC. The selection of mutually exclusive drivers of tumorigenesis may account for some of the differences observed, and this may be due to the correlation between miRNA profiles and the type of the genetic path- ways differently activated in ACC, such as Wnt/ß-catenin signaling, PTEN/AKT/mTOR axis, Notch signaling, Hedgehog signaling, Wnt/Fzd signaling, JAK/STAT signaling, EGFR signaling, P53 mutation, KRAS mutation, and IGF2. Considering their remarkable collaboration in such signaling pathways, miRNAs can be used as indicators of ACC incidence or recurrence.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
CRediT authorship contribution statement
Conception and design: G.K.H., W.A.E., A.I.A., N.M.A., S.S.M., A.S. D., and T.M.A. Collection and/or assembly of data: H.M.M., S.S.E., A.A. E., D.F., and M.S.E. Manuscript writing: M.B.Z., M.A.A., N.I.R., M.A.E., and A.H.H. All authors have read and approved the published version of the manuscript.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
Not applicable.
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