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Studies on the roles of EMT-associated microRNAs in cervical cancer and aggressive endometrial cancer

徐, 道知 北海道大学

2022.06.30

概要

[Background and Purpose]
Cervical cancer (CC) is one of the most common gynecological malignancies. Cancermetastasis begins with the process of epithelial-mesenchymal transition (EMT), whichconvertswell-polarized epithelial cells to non-polarized mesenchymal cells that acquire motilityandinvasion properties and exhibit cancer stem cell-like properties. The 90-kDa heat shockprotein(HSP90) promotes EMT and tumor progression by protecting and stabilizing its client proteins. To date, the exact function of HSP90 in CC development is still unclear. MicroRNAs (miRNAs)function as post-transcriptional regulators of mRNAs by inhibiting the translationof theirrespective RNA targets or degrading their targets. The reduction in miR-361 expressionindiverse tumor types and its tumor-suppressing function has been described. We previouslyreported that miR-361 represses the expression of target genes implicated in EMTandcancerstemness in endometrial cancer (EC). Long non-coding RNAs (lncRNAs) can act as molecularsponges of miRNAs, thereby affecting the expression of target genes of miRNAs. Wedemonstrated that lncRNA NEAT1 drives EC progression by sponging miR-361. Ourmeta-analysis indicated that the 3′-untranslated region (3′-UTR) of HSP90 mRNAcontainsasequence complementary to the seed regions of miR-361. We aimed to explore the roleofmiR-361 in cervical cancer and the mechanisms underlying its function in EMT. We speculatedthat miR-361 directly targets HSP90 to inhibit the invasion and EMT features, andNEAT1functions as an oncogenic lncRNA that suppresses miR-361 expression and induces EMTandsphere formation in CC cells.

[Materials and Methods]
We used an online database to examine the expression of miR-361 in human cervical cancerand normal cervical tissues. The levels of miR-361 in one immortalized but non-malignant human endometrial cell line (EM) and in two human CC cell lines were measured byreal-timePCR analysis. The association between miR-361 expression and the overall survival outcomesin CC patients from the Cancer Genome Atlas cohort was analyzed using online databases. Cell functional assays were used to explore the effects of miR-361 overexpression/knockdownonthe proliferation, invasion, EMT and sphere formation of CC cells. The possible target genesofmiR-361 were predicted using miRNA-target prediction programs. Luciferase reporter assayswere performed to verify the interaction between miR-361, HSP90, and lncRNANEAT1.

[Results]
[1] The expression of miR-361 was downregulated in CC tissues. The levels of miR-361inCC cell lines (HeLa and SiHa) were significantly lower than those in EMcells. Lowerexpression of miR-361 was significantly associated with a poorer prognosis incervical cancer.

[2] Overexpression of miR-361 induced an epithelial phenotype and significantly decreasedcell invasion and sphere formation. However, the knockdown of miR-361 promotedamesenchymal phenotype and greatly increased cancer cell invasion and sphere formation. Upregulation of miR-361 increased the expression of E-cadherin and inhibitedtheexpression of Vimentin in CC cells. Knockdown of miR-361 had opposite effectsonthese genes, suggesting that miR-361 inhibits EMT and sphere formation in CCcells.

[3] HSP90 was predicted as a potential target of miR-361. HSP90 expressionwassignificantly higher in CC tissues and CC cells. CC patients with higher HSP90expression had worse overall survival than those with lower HSP90 expression. Ectopicexpression of miR-361 decreased, while inhibition of miR-361 increased the expressionof HSP90 in CC cells. The luciferase reporter assays demonstrated overexpressionofmiR-361 significantly decreases luciferase activity of the wild-type (WT) HSP90 3′-UTR, and the transfection with miR-361 inhibitor markedly induced the luciferaseactivity of the WT HSP90 3′-UTR in CC cells. However, transfection with miR-361mimic or miR-361 inhibitor had no obvious influence on the luciferase activityof thereporter vector harboring the mutant HSP90 3′-UTR, suggesting that miR-361directlytargets and reduces HSP90 expression in CC cells.

[4] Knockdown of HSP90 reduced mesenchymal phenotype of SiHa cells, andoverexpression of HSP90 in HeLa cells led to mesenchymal-like morphologyandtriggered cell scattering. Downregulation of HSP90 significantly inhibited the invasionand cancer stem cell properties of SiHa cells and overexpression of HSP90 promotedtheinvasion and cancer stem cell properties of HeLa cells. Silencing of HSP90 enhancedtheexpression of E-cadherin and reduced the protein expression of Vimentin. However, overexpression of HSP90 decreased E-cadherin expression and increased Vimentinexpression, suggesting that HSP90 promotes EMT and sphere formation in CCcells.

[5] Our meta-analysis revealed a significantly higher level of NEAT1 in CCsamplescompared with normal samples. The expression of NEAT1 was significantly upregulatedin CC cells compared with EM cells. The depletion of NEAT1 by siRNAsignificantlyupregulated miR-361 levels in CC cells. The luciferase reporter assays verified thedirect binding relationship between NEAT1 and miR-361 in CC cells. Silencing of NEAT1significantly suppressed the expression of HSP90 and Vimentin but increased thelevelsof E-cadherin in CC cells. NEAT1 knockdown led to decreased cell invasion andsphereformation. Taken together, our results support the notion that NEAT1 promotesCCinvasion and sphere formation through up-regulating HSP90 expression by bindingwithmiR-361, a tumor suppressor that directly suppresses HSP90 expression.

[Discussion]
MiR-361 represses tumor progression by targeting multiple components of manyessential signaling pathways implicated in tumor growth, EMT, metastasis, drug resistance, angiogenesisand inflammation. HSP90 is a crucial molecular chaperone that forms a complexwithco-chaperones to promote tumor progression by protecting and stabilizing numerous client proteins. Consistent with these previous reports, our findings supported the complexityofmiR-361-regulated signaling pathways that determine the phenotypes of human tumor cellsand demonstrated that the loss of miR-361 expression elevates HSP90 levels, leadingtotheacquisition of EMT and cancer stem cell-like phenotypes of CC cells. Additionally, HSP90could be secreted by cancer cells, and extracellular HSP90 promotes EMT and cancer cell invasion and stimulates metastatic spread. Therefore, the impacts of miR-361 andNEAT1expression on the secretion of HSP90 by CC cells should be studied using the enzyme-linkedimmunosorbent assay. Whether the secreted HSP90 acts as a pivotal regulator of CCprogression and metastasis requires further investigation. Moreover, the overexpressionofNEAT1 exerts its oncogenic functions in most human cancers by functioning as a molecularsponge for miRNAs. In this study, we demonstrated for the first time that, by competitivelybinding to miR-361 and suppressing its expression, NEAT1 upregulates the expressionofHSP90 to promote EMT, invasion, and sphere formation of CC cells. Future investigationwill be required to determine the mechanisms by which NEAT1 performs this function incervical cancer.

[Conclusion]
MiR-361 directly targets HSP90 to inhibit the invasion and EMT features, andNEAT1functions as an oncogenic lncRNA that suppresses miR-361 expression and induces EMTandsphere formation in CC cells. Our findings provided useful insights into the mechanisms of CCEMT and metastasis.

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