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Pathology - Research and Practice
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PATHOLOGY RESEARCH PRACTICE
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Review
miRNAs orchestration of adrenocortical carcinoma - Particular emphasis on diagnosis, progression and drug resistance
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Walaa A. El-Dakrourya, Heba M. Midan b, Ahmed I. Abulsoud c,d, Shereen Saeid Elshaer d, e, Ahmed A. El-Husseiny “,f, Doaa Fathi ”, Nourhan M. Abdelmaksoudª, Sherif S. Abdel Mageed &, Mohammed S. Elballalb, Mohamed Bakr Zakih, Mai A. Abd-Elmawla 1, Tohada M. AL-Noshokaty , Nehal I. Rizk ”, Mahmoud A. Elrebehyb,“,1, Amr H. Hashem3, Yasser M. Moustafa &,k, Ahmed S. Doghish b,I, ** , 2
a Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829 Egypt b Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
” Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231 Cairo, Egypt
d Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
e 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 % Pharmacology and Toxicology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
h 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 Botany and Microbiology Department, Faculty of Science, Al-Azhar University, Nasr City 11884 Cairo, Egypt
k Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231 Cairo, Egypt
| ARTICLE INFO | ABSTRACT |
|---|---|
| Keywords: MiRNA Adrenocortical carcinoma ACC Drug resistance Diagnosis Prognosis | Adrenocortical carcinoma (ACC) is an uncommon aggressive endocrine malignancy that is nonetheless associated with significant mortality and morbidity rates because of endocrine and oncological consequences. Recent genome-wide investigations of ACC have advanced our understanding of the disease, but substantial obstacles remain to overcome regarding diagnosis and prognosis. MicroRNAs (miRNAs, miRs) play a crucial role in the development and metastasis of a wide range of carcinomas by regulating the expression of their target genes through various mechanisms causing translational repression or messenger RNA (mRNA) degradation. Along |
Abbreviations: ACA, Adrenocortical adenoma; ACC, Adrenocortical carcinoma; ACTs, Adrenocortical tumors; Ago, Argonaute1; Akt, Akt serine/threonine kinase, also known as protein kinase B; Ang II, Angiotensin II; Bcl-2, B-cell lymphoma 2; BIRC5, Baculoviral IAP repeat containing 5; CDC25B, Cell division cycle 25B; CDK1, Cyclin dependent kinase 1; CDKN1A, Cyclin dependent kinase inhibitor 1 A; DGCR8, DiGeorge Critical Region 8; Dicer, An endoribonuclease enzyme that in humans is encoded by the DICER1 gene; Drosha, Double-stranded RNA-specific endoribonuclease; eIF4E, Eukaryotic translation initiation factor 4E; EMT, Epithelial-to- mesenchymal transition; ENSAT, European Network for the Study of Adrenal Tumors; H19, Imprinted maternally expressed transcript (non-protein coding); IC50, Half maximal inhibitory concentration; IGF-1R, Insulin-like growth factor 1 receptor; IGF2, Insulin-like growth factor 2; LIN28A, Lin 28 homolog A; LIN28B, Lin 28 homolog B; MALAT1, Metastasis-associated lung adenocarcinoma transcript1; MATR3, Micro RNA, Matrin 3MiRNA/ MiR-511; mRNA, Messenger RNA; MTDH, Metadherin; mTOR, Mechanistic target of rapamycin; NAC, Normal adrenal cortex; NAG, Non-functioning adrenal tumors; ncRNAs, Non-coding RNAs; NDRG, N-Myc downstream-regulated gene; NDUFC1, NADH ubiquinone oxidoreductase subunit C1; PAX8-AS1, PAX8 Antisense RNA 1; PI3K, Phosphatidylinositol-3-kinase; PKA, Protein kinase A; pre-miRNA, Precursor miRNA; pri-miRNA, Primary miRNA; PUMA, p53 upregulated modulator of apoptosis; RAF1, Raf-1 proto-oncogene serine/ threonine kinase; Ran, RAS-related Nuclear protein; RISC., RNA-induced silencing complex .; RISC, RNA-induced silencing complex; RNA Pol II, RNA polymerase II; RNA, Ribonucleic acid; ROC, Receiver Operating Characteristic; SFPQ, Splicing factor proline and glutamine rich; TARBP2, TAR (transactivation response) RNA binding protein; TCGA, The Cancer Genome Atlas; TRBP, Transactivation response element RNA-binding protein; Wnt, Wingless-type; ZEB1, Zinc finger E-box binding homeobox 1; ZNF367, Zinc finger factor 367.
* Corresponding author.
** Corresponding author at: Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt. E-mail addresses: mahmoud.elrebeihy@buc.edu.eg (M.A. Elrebehy), ahmed_doghish@azhar.edu.eg (A.S. Doghish).
1 https://orcid.org/0000-0002-3574-5518
2 https://orcid.org/0000-0002-0136-7096
https://doi.org/10.1016/j.prp.2023.154665
with miRNAs in the adrenocortical cancerous tissue, circulating miRNAs are considered barely invasive diag- nostic or prognostic biomarkers of ACC. miRNAs may serve as treatment targets that expand the rather-limited therapeutic repertoire in the field of ACC. Patients with advanced ACC still have a poor prognosis when using the available treatments, despite a substantial improvement in understanding of the illness over the previous few decades. Accordingly, in this review, we provide a crucial overview of the recent studies in ACC-associated miRNAs regarding their diagnostic, prognostic, and potential therapeutic relevance.
1. Introduction
Adrenocortical cancer (ACC) is a relatively unusual fatal form of endocrine cancer. The five-year survival rate for adrenocortical carci- noma is only 22%, and the disease occurs at a rate of 0.72-1.02 per million persons annually [1]. ACC may progress silently in 10% of pa- tients, and it is typically diagnosed in most cases at a late stage when curative options are limited [2]. About one-third of patients present with synchronous metastases at initial diagnosis, and the 5-year survival rate is as low as 0% in metastatic ACC patients. The peak diagnosis is in the fourth and fifth decades of life. ACC is slightly more common in women than in men (ratio 1.5: 1), leading to the hypothesis that sex hormones may have an influence on ACC tumorigenesis. The clinical investigations revealed that 50-60% of patients with ACC are having steroid hormone excess (About 50-60% Cushing syndrome, 20-30% hyperandrogenism, and a small fraction of patients have estrogen and/or mineralocorticoid excess). In addition, 30-40% of patients experience space-occupying effects of the tumor mass [3-7]. Normally, microRNAs (miRNAs, miRs) function as epigenetic mediators that adversely affect the protein levels of their target mRNA by translational inhibition or transcript degradation upon binding to the 3’ or 5’ untranslated regions, gene promoter region, or coding sequence [8]. Different disorders have been linked to changes in the expression of miRNAs, which regulate multiple essential critical functions [9-12] including cancer [13-42], liver dis- eases [43], bone diseases [44], cardiovascular diseases [45,46], meta- bolic syndrome [47-49], rheumatoid arthritis [50,51], diabetes [52-55], and coronavirus disease 2019 (COVID-19) infection [56-59], and Alzheimer’s [60,61]. Besides, circulating miRNAs are exciting prospects for cancer biomarkers in various tumor types [14, 18, 20, 24, 27, 36, 62-64]. Despite the rarity of ACC, the function of miRNAs in this carcinoma has lately been a thorough evaluation [65,66]. miRNAs are detectable both inside tumors and outside of them in the bloodstream. Therefore, several malignancies, including ACC, may benefit from using circulating miRNAs as intriguing diagnostic and prognostic biomarkers because of their high stability, persistence, and ease of detection [67-69]. Additionally, miRNAs may be used as therapeutic targets to broaden ACC’s somewhat constrained therapeutic options [70,71]. Even though complete surgical resection provides the best opportunity for long-term survival, ACC has a 50% recurrence rate within two years, posing a therapeutic challenge [72]. Regarding their diagnostic, prog- nostic, and potential therapeutic efficacy, we will give a comprehensive review outlining the present understanding and the most current find- ings in the field of miRNAs dysregulation in ACC and its possible sig- nificance in diagnosing, prognosis, therapy, and managing this malignancy.
To fulfill our aim, the terms “adrenocortical carcinoma” (or “ACC”), “microRNAs” (or “miRNAs”), “drug resistance”, “therapy”, “diagnosis”, and “Prognosis” were used in an online search conducted between January and April of 2023 to identify research publications and reviews published in English over the previous decade. They were located in a variety of medical databases, including ScienceDirect and PubMed. The reviews and original articles were accorded the most weight.
2. miRNAs function and biogenesis
2.1. Function of miRNAs
There is mounting evidence that improper control of non-coding RNA (ncRNAs) processing is essential to carcinogenesis [73-75]. Gene expression is modulated, in large part, by microRNAs and other forms of ncRNA in virtually all eukaryotic organisms. The miRNA production route’s adaptability, control, and interplay with other biological pro- cesses have recently been recognized as contributing to the system’s complexity [76-80].
It has been discovered that mutations in miRNA, particularly, are associated with cancer development. miRNAs play a significant part in the regulation of nuclear as well as mitochondrial genes and proteins. As a result, they can stimulate or inhibit metabolic reprogramming, which can cause or contribute to the development and progression of cancer [81]. Chromosomal rearrangements, epigenetic processes, transcrip- tional dysregulation, chemical modifications and editing, and protein abnormalities have been linked to cancer by miRNA expression changes. RNA-induced silencing complex (RISC) limits miRNA synthesis in several ways. This technique removes miRNAs from the translation machinery. Targeting miRNA and inhibiting translation are examples. This is possible only if the miRNA and target match exactly [80,82,83].
Synthetic miRNA sponges impede miRNA function and accelerate human cell malignancy. miRNAs can regulate the same target or numerous targets. The distinct fingerprints of miRNAs are used to distinguish them [84-87]. miRNAs can encourage or prevent tumor formation depending on the individual cellular expression patterns involved. Furthermore, it may promote metabolic reprogramming, common in malignancies, and the construction of cancer stem cells [88-93].
2.2. miRNAs biogenic pathways
2.2.1. A dive into the canonical pathway of miRNAs biogeny
A series of stages are involved in the maturation of the genes that code for miRNA into its final product. RNA polymerase II transcribes miRNA genes into primary miRNA (pri-miRNA). This pri-miRNA is then subjected to processing by the microprocessor complex, which results in the formation of precursor miRNA (pre-miRNA). Exportin 5 is respon- sible for transporting pre-miRNA to the cytoplasmic partition, where it is then cleaved by Dicer to produce the mature form of miRNA, which is its functional form (Fig. 1) [94-97].
2.2.2. Navigating the non-canonical miRNA biogenesis
Some new frontiers of data point to the idea that some miRNAs go via processing routes that are not considered conventional or canonical. These lines of research have been pointing in this direction for some time now. In the process of partitioning non-canonical miRNA production paths, the following are some generic categories that may be applied as divisional tools: 1) Dicer-independent pathways and 2) Drosha- independent pathways, which include tRNase Z-dependent pathways, endogenous short-hairpin RNAs and small nucleolar RNAs derivatiza- tion, and Mirtrons [98-101].
3. Role of miRNA in initiation, proliferation and progression of ACC (miRNA dysregulation)
Several miRNAs were shown to be deregulated in ACC as compared with adrenocortical adenoma (ACAs) [102]. We found that some miR- NAs are upregulated, and others are downregulated in ACC compared to ACA or normal cells. In this part of this review, we focus on gathering the publications that describe miRNA’s role in the initiation, proliferation, and progression of ACC and their targets (Table 1).
Angiogenesis that continues over time is a necessary component of cancer. Virtually all cancer forms are characterized by abnormal blood arteries [103-105]. One of the main factors controlling the angiogenesis of cancer is the vascular endothelial growth factor (VEGF) [106]. Its receptors (VEGFRs) act as a conduit for its actions. A promising method for treating cancer is the pharmacological suppression of VEGFRs [107-110]. Blood samples from ACC patients showed elevated VEGF levels [111].
There are some upregulated miRNAs in ACC; one of those is miR-9. In a study with adult adrenocortical tumors (ACTs) that includes ACAs and ACCs, Faria et al. analyzed the expression of LIN28 protein and its antagonistic regulator miR-9. miR-9 was shown to be overexpressed in aggressive ACC, and low levels of LIN28 protein expression were linked to relapse in previously treated adult ACCs. In addition, aggressive ACCs had higher levels of LIN28A expression than adenomas or nonaggressive ACCs, indicating that LIN28A was negatively regulated after transcrip- tion [112]. High LIN28A and LIN28B expression levels are seen in several forms of advanced and poorly differentiated cancer [113,114]. Also, LIN28 aids in cancer cells’ survival, proliferation, and invasion [115]. Additionally, LIN28 is overexpressed in various late-stage ma- lignancies and is responsible for reprogramming and pluripotency of cells [116,117].
Another overexpressed miRNA in ACC is miR-21[118]. Cancers in which miR-21 is overexpressed tend to have an aggressive character and a dismal prognosis [119]. According to a screening conducted by Romero et al., the expression levels of miR-21 were discovered to be selectively altered by angiotensin II (Ang II) in H295R cells, which is the ACC cell line. Overexpression of miR-21, stimulated by angiotensin II, led to elevated aldosterone release and cell proliferation [118].
In the pediatric ACT, miR-149-3p expression affects H295A cell
proliferation, cell cycle progression, and adrenocortical tumor out- comes. Da Silva et al. evaluated miR-149-3p in 67 pediatric ACT sam- ples and 19 non-neoplastic adrenal tissues. In H295A cells overexpressing miR-149-3p, cell survival, proliferation, colony forma- tion, and cell cycle were examined. mRNA and protein CDKN1A expression were investigated. miR-149-3p increased cell survival and colony formation, and cell cycle progression. CDKN1A was a miR- 149-3p target gene. Thus, through downregulating CDKN1A, miR- 149-3p increases H295A cell viability and may be a pediatric ACT treatment target [102].
The miRNAs; miR-139-5p and miR-483-5p have been identified as promising biomarkers for the diagnosis and prognosis of ACC due to their upregulation in ACC and association with the progressed disease stage in contrast to ACA or NAG. Most significantly downregulated by miR-483-5p was a member of the N-Myc downstream-regulated gene (NDRG) family called NDRG2. ACC cell lines NCI-H295R and SW13 had their invasiveness and proliferation hampered when miR-483-5p and miR-139-5p expression were downregulated. This increased mRNA and protein expression of NDRG2 and NDRG4, respectively. Thus, miR- 483-5p and miR-139-5p’s oncomiR role in ACC etiology was hypothe- sized [120,121].
The previously mentioned miR-483-5p is considered one of the most studied miRNAs in ACC, miR-483-5p is one of the most essential single- gene malignancy indicators and could be utilized to aid in detection and assessment [122]. Patients with ACC had elevated levels of miR-483-5p in their bloodstream compared to those with benign adenomas [123]. When identifying ACC as distinct from ACA, insulin-like growth factor 2 (IGF2) is an excellent biomarker. ACC cells have been demonstrated to respond to IGF2, and this growth promoter affected their proliferation, metabolic processes, and survival, but not the ability to invade [124, 125]. In their study of ACC, Patterson et al. showed that miR-483-5p and IGF2 were significantly co-expressed [126]. It was demonstrated that IGF2 mRNA levels may be regulated by inhibiting miR-483-5p [127].
The overexpression of IGF2 in ACC is frequently observed because of genetic anomalies affecting the IGF2-H19. One research examined IGF2- H19 in ACC and ACA. ACC overexpressed IGF2’s miR-483-3p and miR- 483-5p, while miR-675 was underexpressed. miR-483-3p, miR-483-5p, and miR-675 were thought to target proteins with harmful expression
Canonical Pathway Of miRNA Biogenesis
Nucleus
Cytoplasm
TRBP
RNA Pol II
DICER
miRNA gene
Transcription
DROSHA
Mature miRNA
AGO2
pri- miRNA
Microprocessor complex
DGCR8
RISC
XPO5
Target mRNA
pre- miRNA
mRNA degredation or translational repression
9
4
7
1
E
4
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| miRNAs | Alteration | Function | Target | System | Ref. |
|---|---|---|---|---|---|
| miR-9 | ↑ | 1 Cancer progression | LIN28A | Clinical | [112] |
| 1 Metastasis | |||||
| t Cell survival & growth | |||||
| 1 Invasion | |||||
| miR-21 | ↑ | 1 Cellular proliferation | Ang II | in vitro | [118] |
| mir-149-3p | ↑ | 1 Cell viability | CDKN1A | Clinical & | [102] |
| 1 Proliferation | in vitro | ||||
| 1 Colony formation, | |||||
| t Cell cycle progression | |||||
| miR-139-5p | ↑ | 1 Aggressiveness | NDRG4 | Clinical & in vitro | [120] |
| 1 Independent growth | |||||
| 1 Migration and invasion | |||||
| miR-483-5p | ↑ | 1 Aggressiveness | NDRG2 | Clinical & in vitro | [120] |
| 1 Independent growth | |||||
| 1 Migration and invasion | |||||
| t Cellular proliferation | IGF2 | Clinical | [126] | ||
| Į Apoptosis | |||||
| 1 Oxygen consumption | 1 IGF2 | Clinical & | [128] | ||
| 1 Glycolysis rates | Į H19 | in vitro | |||
| 1 Mitochondrial respiration | Į complex I and IV Į NDUFC1 | ||||
| miR-483-3p | ↑ | 1 oxygen consumption | 1 IGF2 | Clinical & | [128] |
| 1 glycolysis rates | Į H19 | in vitro | |||
| 1 Mitochondrial respiration | Į complex I and IV Į NDUFC1 | ||||
| t Cellular proliferation | PUMA | Clinical & in vivo | [129] | ||
| Į Apoptosis | |||||
| miR-503 | ↑ | Į G1 cell cycle arrest | Clinical & in vitro | [129] | |
| 1 Cell differentiation | |||||
| miR-195 | ↓ | Į cell proliferation | DICER | Clinical & in vitro | [129,137] |
| t cell apoptosis | TARBP2 | ||||
| 1 G1 cell cycle arrest | DROSHA | ||||
| Į Cellular proliferation | ZNF367 | Clinical & in vitro | [139] | ||
| Į Invasion, | |||||
| Į Migration, | |||||
| Į Adhesion to extracellular proteins | |||||
| Į Cancer progression | |||||
| miR-497 | ↓ | Į Cell proliferation | DICER | Clinical & in vitro | [129,137] |
| 1 Cell apoptosis | TARBP2 | ||||
| 1 G1 cell cycle arrest | DROSHA | ||||
| Į Cellular proliferation, | MALAT1 | Clinical & | [142] | ||
| 1 Cell apoptosis, | eIF4E | in vitro | |||
| Į Migration and invasion | SFPQ | ||||
| MiR-7 | ↓ | Į Cellular proliferation | RAF1 | Clinical & | [131] |
| 1 G1 cell cycle arrest | mTOR | In vitro | |||
| Į ACC growth | CDK1 | ||||
| miR-99a miR-100 | ↓ | Į Cell proliferation | IGFR1 | Clinical & | [146] |
| mTOR | in vitro | ||||
| miR-200b | ↓ | Į Transcription | MATR3 | Clinical & in vitro | [148] |
| Į Proliferation | |||||
| miR-205 | ↓ | Į Cellular proliferation | Bcl-2 | Clinical & in vitro | [149] |
| 1 Apoptosis | |||||
| Į Tumor growth in vivo | |||||
| miR-214 | ↓ | 1 Apoptosis | CDC25B | Clinical & | [133] |
| Į Cell cycle G2/M phase | Bio-informatics | ||||
| miR-335 | ↓ | Į Cell-cycle pathways. | BIRC5 | Clinical & | [154] |
| 1 Apoptosis | PAX8-AS1 | Multi-database analysis | |||
| Immune pathway | |||||
| miR-375 | ↓ | Į Cellular proliferation | MTDH/Akt | Clinical & | [157] |
| Į Tumor invasion and survival Į Metastasis | in vitro | ||||
| Į Chemoresistance | |||||
| miR-431 | ↓ | t Cellular sensitivity to doxorubicin and mitotane | ZEB1 | Clinical & in vitro | [158] |
| Apoptosis and cell cycle Į Cellular proliferation. | |||||
| miR-675 | ↓ | 1 oxygen consumption | 1 IGF2 | Clinical & | [128] |
| 1 glycolysis rates | Į H19 | in vitro | |||
| 1 Mitochondrial respiration | Į complex I and IV Į NDUFC1 |
Akt: Akt serine/threonine kinase, also known as protein kinase B; Ang II: Angiotensin II; Bcl-2: B-cell lymphoma 2; BIRC5: Baculoviral IAP repeat containing 5; CDC25B: Cell division cycle 25B; CDK1: Cyclin-dependent kinase 1; CDKN1A: Cyclin-dependent kinase inhibitor 1 A; eIF4E: Eukaryotic translation initiation factor 4E; H19: H19, imprinted maternally expressed transcript; IGF2: Insulin-like growth factor 2; LIN28B: Lin 28 homolog A; MALAT1: Metastasis-associated lung adeno- carcinoma transcript1; MATR3: Matrin 3; miRNA: Micro RNA; MTDH: Metadherin; mTOR: Mechanistic target of rapamycin; NDRG: N-Myc downstream-regulated gene; NDUFC1: NADH ubiquinone oxidoreductase subunit C1; PAX8-AS1: PAX8 Antisense RNA 1; PUMA: p53 upregulated modulator of apoptosis; RAF1: Raf-1
proto-oncogene serine/threonine kinase; SFPQ: splicing factor proline and glutamine-rich; TARBP2: TAR (transactivation response) RNA binding protein; ZEB1: zinc finger E-box binding homeobox 1; ZNF367: Zinc finger factor 367.
levels. Included are mitochondrial metabolic proteins. ACC had far lower mitochondrial respiratory system complex I and IV than ACA. ACC showed lower protein expression of NADH ubiquinone oxidoreductase subunit C1 (NDUFC1), a mitochondrial respiratory complex I subunit, than ACA and normal adrenals. ACC H19 downregulation enhanced NDUFC1 protein expression, lowered oxygen consumption, and delayed glycolysis. miR-483-5p-inhibited cells had lower respiration and glycolysis rates, indicating lower energy [128].
Another study in ACC was conducted to study miR-483-3p. It is an oncomiR by encouraging cell growth and suppressing cell death in vitro models [129]. Using reporter assays, researchers found that miR-483-3p directly suppresses the p53 upregulated modulator of apoptosis (PUMA) expression across three distinct cell lines [130]. The protein PUMA targets the tumor suppressor protein p53, which blocks pro-survival B-cell lymphoma 2 (Bcl-2) family proteins [131]. In ACC tissue but not in ACA or NAC, PUMA expression was shown to be inversely asso- ciated with miR-483-3p expression [129]. Several cell models have shown that miR-483-3p regulates PUMA expression; this correlation may be generalized to ACC [112].
Another upregulated miRNA in ACC is miR-503. Several reports on miR-503 in adrenal tumors have also been published [122,132,133]. Different cell lines have shown that miR-503 directly regulates the cell cycle and differentiation [134,135]. Overall survival was substantially inversely correlated with miR-503 expression levels in ACC patients [129,136]. Direct targeting of cell cycle regulators by miR-503 has been linked to the induction of G1 cell cycle arrest and enhancement of cell differentiation across a range of cancer cell lines [135]. Upregulated miRNAs in ACC are shown in Fig. 2.
Several miRNAs are downregulated in ACC as miR-195 and miR-497. One research group conducted two miR-195 and miR-497 experiments to determine their significance in ACC in a total of 73 adrenocortical tumors (43 adenomas and 30 carcinomas) and 9 normal adrenal cortices [129,137]. In the first investigation, the over-expression of miR-195 and miR-497 was shown to limit cell proliferation and promote apoptosis in NCI-H295R ACC cells [129]. High concentrations of miR-195 and miR-497 mimics have been used on H295 cells. This treatment inhibited cell proliferation and promoted cell death by decreasing DICER and
TARBP2 mRNA and protein levels. These results suggest that TARBP2 and DICER miRNAs play a carcinogenic function in ACC [121,129]. In the second study, the central players in the miRNA biogenesis path- way-DROSHA, DICER, and TARBP2 -had their mRNA expression levels analyzed. The results demonstrate that TARBP2, DICER, and DROSHA are significantly over-expressed in carcinomas as opposed to adenomas and adrenal cortices. The protein content findings were similar. Reducing cell proliferation and inducing apoptosis were addi- tional effects of TARBP2 expression suppression in human NCI-H295R ACC cells. miR-195 and miR-497 were shown to directly influence TARBP2 and DICER expression in ACC cells [137].
Moreover, It has been established that miR-195 is repressed in ACC [129,138]. Overexpression of zinc finger factor 367 (ZNF367) was shown in ACC by Jain et al. compared to controls and benign tumors. ZNF367 reduced cell growth, invasion, migration, and adherence to extracellular proteins both in vitro and in vivo. They also demonstrated that miR-195 governs cellular invasion and that there is a malicious link between ZNF367 and miR-195 expression. They hypothesized that ZNF367 expression would rise due to miR-195 downregulation, along with the idea that the miR-195-ZNF367 axis plays a crucial role in preventing cancer development [139].
In the same consequences, metastasis-associated lung adenocarci- noma transcript1 (MALAT1) is known to increase cellular proliferation, apoptosis, migration, and invasion and is overexpressed in several tumor kinds, including ACC [140,141]. In 2019, researchers found the miR-49/MALAT1 feedback axis in ACC tumorigenesis for the first time. The study found that lncRNA MALAT1 was considerably overexpressed in ACC, while miR-497 was dramatically downregulated [142]. Eukaryotic translation initiation factor 4E (eIF4E) is required for protein synthesis because it guides ribosomes to the cap structure of mRNAs. miR-497 overexpression and MALAT1 knockdown reduce eIF4E expression in H295R [143]. They also demonstrated that down- regulating EIF4E expression through silencing MALAT1 and over- expressing miR-497 inhibited cell growth and triggered cell cycle arrest. In addition, MALAT1 has several functions in ACC pathophysiology as evidenced by its direct binding to SFPQ (splicing factor proline and glutamine-rich) protein [142,144]. Additional research using in vitro
Role of miRNAs in initiation, proliferation and progression of ACC (miRNA upregulated)
ACC
miR-9
miR-21
miR-149-3p
miR-139-5p
miR-483-5p
miR-483-3p
miR-503
LIN28A
Ang II
CDKN1A
NDRG4
NDRG2
IGF2
PUMA
Proliferation î
Cell survival î Migration î
Apoptosis Į Proliferation î
Cell viability î Colony formation î Cell cycle progression î
Aggressiveness 1 Growth Î Migration & invasion î
G1 cell cycle arrest ! Cell differentiation î
ACC models demonstrates a reciprocal inhibitory link between miR-497 gain of function and MALAT1 knockdown [145].
miR-7 is one miRNA that is lacking in ACC [138]. Glover et al. conducted research demonstrating that miR-7 inhibits tumor growth in ACC. In vitro, studies have shown that miR-7 inhibits cell growth and causes a G1 cell cycle to stop. The proliferation of ACC xenografts derived from ACC cell lines and primary ACC cells is suppressed by systemic restoration of miR-7. The Raf-1 proto-oncogene ser- ine/threonine kinase (RAF1) and the mechanistic target of rapamycin (mTOR) are direct mechanistic targets of miR-7. In addition, cyclin-dependent kinase 1 (CDK1) is suppressed by miR-7 treatment in vivo. CDK1 is overexpressed in ACC patient samples, while miR-7 expression is negatively linked. In conclusion, miR-7 suppresses a vari- ety of oncogenic pathways, including the lowering of RAF1 and mTOR levels and the suppression of CDK1 activity, hence slowing the devel- opment of ACC [131].
In pediatric ACC tissue samples, miR-99a and miR-100, which are members of the same family, were underexpressed in comparison to NAC, and their expression was inversely linked with that of mTOR and insulin-like growth factor 1 receptor (IGF-1R) mRNA [146]. The IGF-1R/mTOR pathway plays a critical role in controlling adrenocor- tical cell proliferation, which is regulated by these miRNAs at several levels [147]. In vitro studies were performed on the adrenocortical cancer cell line (H295R). miR-200b reduced the expression of Matrin 3 (MATR3), a nuclear protein involved in the regulation of transcription and in the protein kinase A (PKA) signaling pathway, potentially contributing to proliferation and carcinogenesis [148].
It was shown that miR-205 was significantly downregulated in ACC. According to research published in 2015 by Wu et al., miR-205 expression is considerably reduced in ACC tissues compared with ACAs, and this results in apoptosis and impaired proliferation in vivo and also affect the cellular proliferation of ACC SW-13 cells in vitro. Furthermore, they demonstrated that miR-205 inhibits ACC SW-13 cell expansion by repressing the expression of the anti-apoptotic gene B-cell lymphoma 2 (Bcl-2) [149].
It has been observed that miR-214 is also down-regulated in adult ACCs [126,129,133]. Tombol et al. discovered a lack of miR-214 expression in ACC tissue samples. Possible tumor suppressor function for miR-214 in ACC due to association with decreased apoptosis, a
hallmark of malignancy [133,150,151]. Overexpression of cell division cycle 25B (CDC25B), a cell cycle activator implicated in the G2/M transition, was seen in ACC samples and was associated with decreased miR-214 expression [133].
Compared to normal adrenal tissues and ACA, ACC had considerably lower miR-335 expression [152,153]. There is evidence that baculoviral IAP repeat containing 5 (BIRC5) is overexpressed in ACC. BIRC5, also called survivin, is an inhibitor of apoptosis that has been linked to the immune system’s activity [154]. miR-335-5p downregulation is linked to enhanced metastasis and invasion in several cancer types; it has been previously recognized as a biomarker of ACC in contrast to ACA [155]. Poor longevity in ACC was linked to the BIRC5-miR335-5p-PAX8-AS1 network, according to a study of mRNA-miRNA-lncRNA pathways [154]. Downregulated miRNAs in ACC are demonstrated in Fig. 3.
Underexpression of the tumor-suppressing miR-375 is a hallmark of ACC [133]. Metadherin (MTDH) promotes tumor invasion, metastasis, and chemoresistance and is suppressed by in vitro overexpression of miR-375. It promotes cellular proliferation, invasion, and survival via the PI3K/Akt and Wnt/-catenin pathways [156]. miR-375 targets the MTDH/Akt pathway to affect cell proliferation, as evidenced by lucif- erase reporter tests in H295R cells demonstrating that miR-375 directly binds MTDH mRNA and regulates its expression in vitro in ACC [157].
The involvement of miR-431 in the etiology and progression of human malignancies has led to its classification as one of the miRNAs that affect cancer cells. Kwok et al. conducted research using ACC clinical samples in 2019 [158]. Tumors that are responsive to chemo- therapy have higher levels of miR-431 compared to those that are resistant. Researchers found that overexpressing miR-431 in H295R and primary ACC cells reduced the Half maximal inhibitory concentration (IC50) of doxorubicin and mitotane to suppress cellular growth through gain-of-function tests. Epithelial-to-mesenchymal transition (EMT) was inhibited by miR-431 in doxorubicin-treated cells. It was previously discovered that miR-431 in hepatocellular carcinoma directly targets the EMT-inducing protein zinc finger E-box binding homeobox 1 (ZEB1) [159]. H295R cells overexpressing miR-431 showed downregulation of ZEB1 mRNA and protein expression in response to doxorubicin, demonstrating the functionality of this regulatory connection in ACC [158].
Role of miRNAs in initiation, proliferation and progression of ACC (miRNA Downregulated)
ACC
miR-195
miR-497
MIR-7
miR-200b
miR-214
miR-335
miR-375
miR-675
miR-99a miR-100
miR-205
miR-431
MALAT1 elF4E SFPQ
RAF1 mTOR CDK1
MATR3
CDC25B
MTDH/ Akt
ZEB1
H19 complex I & IV NDUFC1
ZNF367
DICER TARBP2 DROSHA
IGFR1 mTOR
Bcl-2
BIRC5 PAX8-AS1
Į Cell proliferation î Cell apoptosis 1 G1 cell cycle arrest
î Apoptosis Į Cell-cycle pathways
Į proliferation
1 Cellular sensitivity to doxorubicin and mitotane
Į proliferation î Apoptosis
î Apoptosis
Į proliferation
Į Proliferation
Į Invasion
Į Cellular proliferation 1 G1 cell cycle arrest Į ACC growth
Į proliferation Į Invasion
Į Migration
Į survival
î oxygen consumption
Į Cancer progression
Į Metastasis
î glycolysis rates
Į Chemoresistance
t Mitochondrial respiration
4. Resistance to the major treatment
miRNAs are essential in developing or inhibiting resistance against different therapies in ACC. In a cohort study followed by in vitro inves- tigation of adrenocortical cancer patients with stage IV that was found to be resistant to doxorubicin, mitotane, and radiotherapy, miR-431 is downregulated. The gain of miR-431 function could sensitize cells to doxorubicin, mitotane, or radiotherapy through targeting ZEB1 (Fig. 4) [160].
5. The clinical importance of miRNAs in ACC
5.1. Diagnosis
miRNAs have the potential to serve as biomarkers due to their tissue- specific nature and susceptibility to dysregulation in a variety of disor- ders, including cancer. In addition, miRNAs exhibit exceptional stabil- ity, rendering them amenable to isolation from formalin-fixed paraffin- embedded specimens and various biological fluids [67]. According to Tömböl et al., it was the first research team to identify ACC’s tissue miRNA expression profile. The study revealed a significant up-regulation of tissue miRNAs, namely miR-503, miR-210, and miR-184, as well as a down-regulation of miR-511, miR-214, and miR-375 in ACC samples when compared to ACA samples. The miRNA MiR-503 exhibited the highest level of overexpression, while MiR-511 demonstrated the most significant downregulation. The dissimilarity between the two miRNAs presents a potential application as a diagnostic indicator for distinguishing between ACC and ACA. The sensitivity and specificity values for this marker are 100% and 97%, respectively, as shown in Table 2. Nonetheless, it is noteworthy that the present study had a restricted sample size of ACCs (n = 7) [161]. In a larger sample, Soon et al. observed significantly reduced levels of miR-195 and miR-335 in ACCs compared to ACAs. A study observed that miR-7 was significantly downregulated in both ACA and ACC compared to the regular adrenals [162]. A recent investigation has revealed that miR-139, miR-335, and miR-675 exhibited a decreased expression in ACC compared to ACA [163]. The expression levels of miR-100,
| miRNAs | Expression | sample | AUC | Sp% | Sn% | Ref. |
|---|---|---|---|---|---|---|
| miR-511 | 11 | Tissue | 0.985 | 93 | 100 | [161] |
| miR-184 | 11 | Tissue | 0.970 | 80 | 100 | [161] |
| miR-100 | 44 | Tissue | 0.717 | [164] | ||
| miR-125b | 44 | Tissue | 0.763 | [164] | ||
| miR-195 | 11 | Tissue | 0.771 | [164] | ||
| Plasma | 0.948 | 100 | 90.9 | [171] | ||
| miR-210 | 11 | Tissue | 1.000 | [172] | ||
| Plasma | 0.87 | 75 | 88.9 | [173] | ||
| miR-335 | 11 | Tissue | 0.877 | 88 | 88 | [171] |
| Plasma | 0837 | 71.4 | 95.2 | [171] | ||
| miR-421 | 11 | Tissue | 0.954 | [172] | ||
| miR-450a-5p | 11 | Tissue | 0.974 | [172] | ||
| miR-483-3p | 11 | Tissue | 0.943 | 80 | 100 | [171] |
| Plasma | 0.917 | 100 | 83.3 | [174] | ||
| miR-503 | tt | Tissue | 1 | 100 | 100 | [175] |
| miR-139-5p | 44 | Plasma | 0.714 | 65 | 87.5 | [176] |
| miR-376a | 11 | Plasma | 0.811 | 85.7 | 71.4 | [123] |
miR-125b, and miR-195 were observed to be down-regulated in ACC. However, miR-483-5p exhibited up-regulation and could distinguish between ACC and ACA with a sensitivity and specificity of 80% and 100%, respectively, as reported in a previous study [164]. The study conducted by Zata and colleagues revealed an upregulation of miR-483-5p, miR-483-3p, miR-210, and miR-21 in ACC [165], as shown in Table 2.
The findings of an integrated genome-wide investigation indicated that miR-9, miR-25, miR-124, miR-183, miR-185, and miR-206 exhibi- ted overexpression in ACC relative to ACA and were associated with reduced gene expression in no less than 10 ACC genes [166]. In a recent study on tissue miRNA, Koperski et al. identified several miRNAs (miR-503-5p, miR-483-3p, miR-483-5p, miR-210, miR-450a, and miR-421) that were significantly up-regulated and shared similarities with those previously reported in ACC vs. ACA. The diagnostic efficacy of miRNAs expressed differentially to a significant extent was evaluated using ROC analysis. The authors of the study recommended the use of miR-483-3p, miR-483-5p, and miR-210 in molecular testing for ACCs
ACC cell
Microenvironmental stimuli as (TGF-B)
IR
P ATM
miR-431
ZEB1
P
ZEB1
CtBP
E-cadherin
USP7
IL912
HUGL2
CHK1
PATJ
EMT
DNA repair
Cell survival
Cell cycle arrest
Doxorubicin
Mitotane
Drug Resistance
Radioresistance
Cancer metastasis
due to their higher mean expression levels compared to other miRNAs, even though the area under the curve for miR-503-5p was 100% as showed in Table 2 [167-169].
The plasma of ACC patient’s expression levels of miR-335 and miR- 195 were significantly down-expressed in ACC, while miR-139, miR- 376a, -b, -c, and miR-483-5p were significantly up-regulated in ACCs compared to ACAs. The plasma of ACC patients exhibited significant overexpression of five miRNAs (miR-100, miR-181b, miR-184, miR-210, and miR-483-5p) compared to ACA patients. In a subsequent study, the absolute plasma concentration of miR-483 and miR-483-5p was evalu- ated, revealing a significant upregulation in advanced stages of ACC (stagesIII-IV) compared to localized malignancy (stages I-II), adreno- cortical adenoma, and individuals without the disease as shown in Table 2 [170]. Additionally, a correlation has been established between the level of miR-483-5p and the number of circulating tumor cells. A recent study evaluated the diagnostic efficacy of miR-483-5p derived from both urine and whole plasma [123]. The study found a significant upregulation of miR-483-5p in the entire plasma of individuals with ACC compared to those with ACA. However, while miR-483-5p was detectable in urine, there was no discernible variation in urinary miR-483-5p between ACC and ACA, as shown in Table 2 [123].
5.2. Prognosis
Adrenocortical carcinoma is rare cancer with a poor prognosis due to a lack of potent and durable treatments, making this cancer an aban- doned disease [177]. The Cancer Genome Atlas (TCGA)-Pan-Cancer project recently conducted a survival analysis, and the results showed that ACC had an intermediate prognosis compared to several other neoplasms [178]. The prognosis of ACC varies depending on the tumor stage, with a 5-year survival rate that ranges from about 84% for tumors with European Network for the Study of Adrenal Tumors (ENSAT) phase I to 15% for tumors with ENSAT stage IV [179]. The prognosis of ACC may also be affected by factors other than the ENSAT stage, including age [180], tumor excision status[181], cortisol production and secretion [182], Ki-67 indices [183], and genetic markers [184,185].
Intratumorally and in circulation, miRNAs can be detected [69,186]. Circulating miRNAs are attractive diagnostic, prognostic, and thera- peutic parameters in various tumors, including ACC, since they are easily recognized and highly reliable [67,72]. Only a few miRNAs can currently be used as prognostic biomarkers in ACC patients [187]. Chabre et al. found that low levels of miR-195 were highly predictive and prognostic of aggressive ACC [171]. In another study on ACC pa- tients, those with lower postoperative miR-483-5p levels had signifi- cantly longer recurrence-free and overall survival rates than those with higher miR-483-5p levels [188]. miR-503, miR-1202, and miR-1275 have significant prognostic potential in ACC and are associated with
| miRNA | Biomarker role | Expression levels | Specimen | Ref. |
|---|---|---|---|---|
| miR-195 | Prognosis | Downregulation | Serum | [171] |
| miR-483-5p | Prognosis | Upregulation | Tumor/ | [188] |
| Serum/ Plasma | ||||
| miR-503 | Prognosis | Upregulation | Tumor | [189] |
| miR-1202 | Prognosis | |||
| miR-1275 | Prognosis | |||
| miR-210 | Prognosis | Upregulation | Tumor | [191] |
| miR-503 | Prognosis | Upregulation | Tumor | [175] |
| Combination of | Diagnosis | Downregulation/ | Tumor | [193] |
| miR-511/ | and/or | Upregulation | ||
| miR-503 | prognosis | |||
| Combination of | Diagnosis | Downregulation/ | Tumor | [175] |
| miR-34a/ miR- | and/or | Downregulation | ||
| 497 | prognosis |
poor survival in ACC patients, as shown in Table 3 [189].
Numerous studies demonstrated that miR-210 is overexpressed in ACC relative to ACA and normal adrenal cortex (NAC) [190,191], and it is also significantly highly expressed in ACC with distant metastasis [175]. Overexpression of miR-210 was also associated with poor prog- nosis [192]. Other studies on adrenal tumors have also described miR-503 [175,189,193], and it has been demonstrated that an increase in tumor growth correlates with miR-503 overexpression [175,189].
Novel miRNA combination panels have been recently established as markers of malignancy and were considered a good guide for cancer diagnosis and/or prognosis [194]. The combination between miR-511 and miR-503 yielded 100% sensitivity and 97% specificity in ACC [193]. Another study found that combining miR-34a and miR-497 had a 100% sensitivity and 96% specificity for differentiating ACC from ACA (Table 3) [175].
6. Future prospective and research direction
The discovery of miRNAs has radically altered our knowledge of gene regulation, and recent research has demonstrated that miRNAs play crucial roles in the molecular biology of cancer. Like many others, ACC is associated with alterations in the expression and activity of miRNAs [186]. Expression dysregulation of miRNAs disrupts the ho- meostasis balance of proteins involved in the pathways that regulate cell cycle progression, cellular proliferation, apoptosis, and chemo- resistance. When oncogenic miRNAs are overexpressed, and tumor suppressor miRNAs are underexpressed, carcinogenesis is promoted [195]. Our current knowledge of the tumor biology of ACC and the molecular pathways involved may be improved by more investigation into the function of miRNA regulation in the disease.
IsomiRs are miRNA sequences that have variations with respect to the reference sequence [196,197]. Improvements in diagnosis accuracy using methods like miRNA liquid biopsy are possible because of small RNA sequencing of isomiRs and a more profound knowledge of the miRNA signature of ACC [72]. The present poor prognosis of these in- dividuals may be improved by exploring innovative miRNA-based therapy approaches, which will become viable as functional methods keep developing and molecular connections can be identified.
7. Conclusion
The altered expression of miRNAs has been described in several studies of ACC. Their implication in ACC is relevant, and their diagnostic utility is promising both as tissue and circulating biomarkers, where ACC opens the door for more precise diagnostic methods such as miRNA liquid biopsy. Despite significant advances in our understanding of ACC, the outlook for individuals with advanced illness remains bleak. There is an excellent potential for miRNAs in cancer treatment, but the clinical applicability of direct miRNAs targeting ACC seems to be, however, quite far away. The current dismal prognosis of these individuals can be improved by exploring innovative miRNA-based therapy methods made feasible by the ongoing development of functional techniques that allow molecular interactions to be identified. Further research on more sig- nificant cohorts with standardized methodologies is required to evaluate the clinical applicability of circulating miRNAs in ACC. However, they appear to be the most promising modalities.
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: 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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