Genetic and Methylation-Induced Loss of miR-181a2/181b2 within chr9q33.3 Facilitates Tumor Growth of Cervical Cancer through the PIK3R3/Akt/FoxO Signaling Pathway

Abstract

Purpose: Loss of Chr9q31-33 is one of the most common chromosome imbalances of cervical cancer, but the underlying mechanism has not been well documented.Experimental Design: The loss of heterozygosity (LOH) status of Chr9q31-33 was investigated utilizing 26 microsatellite markers. We detected the expression of miR-181a2/181b2 by qRT-PCR analysis of cervical cancer cell lines and 100 paired tumor samples and corresponding adjacent non-tumor tissues. Kaplan-Meier and Cox proportional hazard regression analyses were performed to identify the prognostic value of miR-181a2/181b2. Regulation of expression was analyzed by methylation-specific PCR. The tumorsuppressing effects of miR-181a2/181b2 were determined in vitro and in vivo. The target gene and signaling pathway that mediated the function of miR-181a2/181b2 were also identified.Results: Chr9q33.3 was identified as one of the most deleted regions in cervical cancer. Underexpression of miR-181a2/ 181b2 was detected in 46% of cervical cancer and was induced by the LOH of chr9q33.3 and promoter hypermethylation. Attenuated miR-181a2/181b2 expression predicted a poor prognostic phenotype and advanced clinical stage of cervical cancer. miR-181a2/181b2 prominently dampened cell-cycle progression, suppressed cell growth, and promoted apoptosis of tumor cells in vitro. They also effectively impeded tumor formation and growth in vivo. miR-181a2/181b2 exert the tumor suppressor ability by depressing the direct target PIK3R3 (p55g) and consequently modulating the PIK3R3/Akt/FoxO signaling pathway.Conclusions: We demonstrated a cause-and-effect event beginning from loss of chr9q33.3, a frequent event in cervical cancer, to the underexpression of miR-181a2/181b2, leading to the elevated activation of the PI3K pathway.

Phase Ib/II study of safety and efficacy of low‐dose decitabine‐primed chemoimmunotherapy in patients with drug‐resistant relapsed/refractory alimentary tract cancer

“…The gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed based on the top 10 differentially expressed miRNAs. The quantification of miRNAs of the plasma samples of the other 42 patients using real‐time polymerase chain reaction was then conducted separately as described previously 33. The primers used are shown in Supporting Information Table S1.…”

Role of PI3K/AKT pathway in cancer: the framework of malignant behavior

“…In particular, the mutations of PIK3CA E542K and E545K promote glycolysis and proliferation of CC in vitro and vivo [212]. NBPF1, ARHGAP17, miR-99b, -181a2/181b2, -338, -383, -433 and -489, as well as LncRNA ANRIL, CRNDE, NEAT1 and LINC01305 are involved in the proliferation, invasion, autophagy or EMT via PI3K/AKT pathway [213][214][215][216][217][218][219][220][221][222][223][224]. Currently, only preclinical trials of PI3K inhibitor LY294002 has revealed it significantly radiosensitized CC cell lines in vitro and vivo [225,226], and the terminated clinical trials of AKT inhibitor GSK2141795 (NCT01958112, Table 3) has tried to display a novel treatment approach to patients of CC.…”

Methylation‑associated silencing of miR‑638 promotes endometrial carcinoma progression by targeting MEF2C

“…In terms of tumor-suppressive miRNAs, aberrant methylation in the cpG islands of their promoters, was demonstrated to be one of the most common epigenetic mechanisms that modulated their expression and biological function (2). A number of miRNAs, including miR-132, miR-148a, miR-107, miR-181 and miR-34, have been identified to be epigenetically silenced by the hypermethylation of cpG islands in/near the promoter region (3)(4)(5). However, miRNA methylation status in endometrial carcinoma (Ec) has not been comprehensively investigated.…”