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Hypoxia Regulated Mir-210 in Cancer

Hypoxia Regulated Mir-210 in Cancer

INTRODUCTION

In numerous physiological processes and pathological situations, including cancer, Parkinson’s disease, cardiac ischemia/reperfusion, and stroke, Hypoxia is recognized to play a crucial role[1]. The hypoxia inducible factor-1α (HIF-1α) may affect mitochondrial function and activate different signalling pathways in a hypoxic environment[1]. The HIF-1α activation causes miR-210’s overexpression and the resultant modification of cellular processes, including cell cycle regulation, mitochondria function, apoptosis, angiogenesis and metastasis[2].

MicroRNAs (miRNAs) are short non-coding RNAs that control gene expression post-transcriptionally by pairing to 3′ untranslated regions, coding s5′ UTRs of target messenger RNAs, which in maximum cases causes translation inhibition or mRNA degradation[3]. In mammals, miRNAs are prophesied to regulate the activity of around 50% of all protein-coding genes [3]. Due to the widespread controlling functions, miRNAs are involved in almost all cellular processes, including differentiation, cell proliferation, cell death, and tumorigenesis[3]. 

miR-210 is an intronic miRNA that resides within the genomic loci of transcript AK123483[3]. While most studies informed miR-210 regulation in a hypoxia-inducible factor-1 (HIF-1)-dependent way, HIF-2-dependent and HIF-independent regulation of miR-210 has also been described[3]. 

miR-210 FUNCTION AS ONCOGENE

Since miR-210 is all-around and strongly regulated in hypoxic cells, and Hypoxia is a fundamental characteristic of strong tumours, the roles of miR-210 in carcinogenesis may be explored reasonably[3].

(A) Promotes cancer cell proliferation:-

Sustaining proliferative capacity is a crucial characteristic of cancer cells that develop such ability in many ways-

(1) produce growth factor ligands and stimulate normal cells to supply different growth factors to the tumour-associated stroma[3].

(2) harbour activating mutations to sustain proliferative signalling[3].

(3) interrupt the negative feedback loops that attenuate proliferative signalling capacity[3].

In recent years, there has been considerable interest in hypoxia-induced MIR-210 in regulating cell cycles and has provided reliable proof supporting a role for miR-210 in promoting cancer cell proliferation[3]. The MNT(Max’s Next Tango), known as the MYC antagonist, was designated as the MIR-210 target by Zhang and his colleagues[3]. Mir-210’s overexpression can override the inhibition and proliferation of hypoxia-induced cancer cells by directly downregulating MNT and indirectly activating c-MYC[3].

Similarly, but differently, Yang and colleagues showed that downregulation of miR-210 in hypoxic human hepatoma cells causes the cell cycle to arrest in the G0/G1 phase, resulting in decreased cancer cell proliferation[3]. But, functional targets of miR-210 contributing to such an effect need further research[3].

(B) Elevated miRNA-210 disrupts DNA repair and causes genetic instability:- 

There is a more prominent instance of aneuploidy in miR-210-overexpressing cells than in normal cells[2]. Hypoxic cells are susceptible to genetic instability, aneuploidy, higher rates of DNA mutation and are affected by their capacity to repair aberrant DNA [4]. Current data shows that insufficient DNA repair is mainly caused by downregulation of DNA repair genes in hypoxic conditions and is commonly involved in tumorigenesis, consisting of BRCA1, RAD51, RAD52 and BRCA2 and members of the Homology-Dependent Repair (HDR) DNA repair pathway[2].

Following the recruitment of replication protection A (RPA), the HDR route repairs complicated double-strand lesions by recruiting RAD 51 and BRCA2 proteins at the breaking point[2]. In BRCA2-deficient cells, including some types of breast cancer, RAD52 substitutes for the lost BRCA2 by recruiting RAD51 to the place of DNA breaks, suggesting that BRCA2 and RAD52 play very related roles in the HDR pathway[2]. In hypoxic cells, miR-210 binds to two sites on the 3′ UTR of the RAD52 mRNA causing RAD52 mRNA degradation and rendering it incapable of participating in DNA repair by the HDR pathway[2].

(C) miR-210 inhibits apoptosis:-

Hypoxic cancer cells are known for their resistance to radiotherapy and many standard chemotherapeutic agents, of which the underlying mechanisms remain to be exposed[3]. As the master HRM(hypoxia-regulated miRNA), the correlation of miR-210 and apoptosis and cell survival was laboriously investigated[3]. In a wide variety of studies, it was shown that not only cancer cells but normal healthy cells such as human pulmonary artery smooth muscle cells(HPASMC), cardiomyocytes, bone marrow-derived mesenchymal stem cells, and neural progenitor cells have antiapoptotic and cytoprotective effects[3].

(D) miR-210 induces metastasis and angiogenesis:-

Angiogenesis, the process by which migratory endothelial cells form new blood vessels from pre-existing blood vessels, is responsible for rendering tumour sustenance and supporting cancer metastasis[2]. It has been shown that Hypoxia can result in angiogenesis, suggesting the potential for miR-210-mediated regulation of endothelial cell angiogenesis[2]. Interestingly, the miR-210-mediated effect on endothelial cell angiogenesis is associated with the mir210-induced impacts on mitochondrial metabolism, where miR-210 overexpression favours the switch from oxidative phosphorylation to lactic acid fermentation[2]. The miR-210-induced switch results in an increase in glucose transporters, namely GLUT-1, whose presence makes up for decreasing glucose during glycolysis[2]. GLUT-1 upregulation is followed by upregulation of the Vascular Endothelial Growth Factor (VEGF) and Platelet-Derived Growth Factor (PDGF), producing an extracellular environment primed for angiogenesis[2]. 

In addition to enhanced angiogenic potential, cells overexpressing hypoxia-induced miR-210 own significantly higher invasion potential than normoxic cells[5]. miR-210 influences angiogenesis and metastasis by targeting and negatively regulating vacuole membrane protein 1 (VMP1), which usually functions by restraining cell migration and invasion[2]. Overexpression of miR-210 resulted in a reduction in VMP1 mRNA and protein levels in colorectal cancer and hepatocellular carcinoma, encouraging enhanced cell migration and invasion, which is supported by studies of miR-210 knockdown in which cellular migration and invasion were inhibited[2].

(E) miR-210 induces immunosuppression:-

Cancer cells have evolved several ways to avoid immune monitoring throughout the initiation and progression of cancer[3]. Emergent data has revealed that specific miRNAs influence genes’ expression in the innate and adaptive immune response[3]. Recent research studied the function of miR-210 in the induction of immunosuppression in hypoxic carcinogenic cells in hypoxic zones of human tumour tissue[6]. They examined the sensitivity of IGR-Heu (human NSCLC cell line) and NA-8 (human melanoma cell line) cells in which anti-miR-210 had dissolved miR-210 expression to cytotoxic T cells (CTC)-mediated lysis under Hypoxia, explained that these cancer cells were more susceptible to CTC-mediated lysis, implying the immunosuppressive effects of miR-210 in hypoxic cancer cells[6]. Functional analysis has recognized the potential targets of miR-210, including PTPN1, HOXA1 and TP53I11, that give immunosuppression to hypoxic cells[6].

miR-210 AS TUMOUR SUPPRESSOR

Although miR-2210 supports the growth of cells in many malignancies, a small number of cancer cells, including ovarian cancer, ESCC (Esophageal Squamous Cell Carcinoma) and Laryngeal Squamous Cell Carcinoma (LSCC) were also found to perform a tumour suppressive function[2]. MiR-210 levels are kept at relatively small levels for ovarian cancer because of the loss of gene copy[2]. While the exact effects of this are unknown, evidence from other miR-210 tumour suppressor investigations gives insights into how the mechanism of tumour suppression is carried out[2].

miR-210 AND MITOCHONDRIAL METABOLISM

Under hypoxic conditions, cell metabolism changes from mitochondrial oxidative phosphorylation to glycolysis[3]. HIF-1 plays a crucial role in this by up-regulating the expression of maximum glycolytic enzymes and pyruvate dehydrogenase kinase while down-regulating the respiration process in mitochondria[3]. As tumours primarily rely on glycolysis even under normal oxygen supply, which is significantly different from normal cells, the underlying molecular mechanisms deserve additional investigation[3].

The control of mitochondrial metabolism during Hypoxia by miR-210 was first described by Chan et al. [3]. They used pulmonary arterial endothelial cells as a representative hypoxic cell type, describing that miR-210 directly targets iron-sulfur cluster assembly proteins (ISCU 1/2) and reduces prototypical iron-sulfur proteins’ activity mitochondrial metabolism, including ComplexIand aconitase, resulting in limited oxidative phosphorylation[3]. As miR-210 is very stable, when hypoxic cells undergo reoxygenation, HIF-1α is degraded rapidly, but miR-210 remains stable to maintain glycolytic phenotype and inhibit mitochondrial metabolism under normoxia[3]. Such advantages may be used by cancer cells, contributing to the Warburg effect[3]. 

miR-210 AS DIAGNOSTIC AND PROGNOSTIC BIOMARKER OF CANCER

To enhance treatment outcomes, early diagnosis and prognosis evaluation of cancer are essential[3]. It is well approved that cancer cells or tissues harbour aberrant miRNA expression profiles related to normal cells or tissues[3]. Specific miRNA signatures can be utilized to diagnose and classify cancer patients into subgroups with distinct prognoses supervising individualized treatment[3]. However, various studies have examined the role of miR-210, which seem to be contradictory, in cancer detection and prognosis[3].

Most evidence displayed miR-210 was up-regulated in many solid tumours, including breast cancer, head cancer and neck cancer, pancreatic cancer, lung cancer, renal cancer, lymphoma, osteosarcoma, and esophageal cancer as ovarian cancer[3].

Because of the inherent stability of miRNAs and the high sensitivity, as well as specificity of quantitative RT-PCR, samples utilized for diagnosis include not only tumour tissue but also a serum, sputum, plasma and stool that are readily available in the clinic, showing the promise of miRNAs in clinical application[3]. Notably, the diagnostic power improved when using multiple miRNAs rather than only one MIRNA

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