MiR-335 Restrains the Aggressive Phenotypes of Ovarian Cancer Cells by Inhibiting COL11A1.

Tzu-Hao Chang,Cheng-Yang Chou,Pei-Ying Wu,Soon-Cen Huang,Tsung-Ying Hsieh,Yu-Fang Huang,Sheng-Yen Hsiao,Yi-Hui Wu

doi:10.3390/cancers13246257

Abstract

Simple SummaryHigh collagen type XI alpha 1 (COL11A1) levels are associated with tumor progression, chemoresistance, and poor patient survival in several cancer types. We examined the role of miRNAs in regulating COL11A1 expression. This study highlighted the importance of miR-335 in downregulating COL11A1-mediated ovarian tumor progression, chemoresistance, and poor survival and suggested its potential application as a therapeutic target.High collagen type XI alpha 1 (COL11A1) levels are associated with tumor progression, chemoresistance, and poor patient survival in several cancer types. MicroRNAs (miRNAs) are dysregulated in multiple cancers, including epithelial ovarian carcinoma (EOC); however, the regulation of COL11A1 by miRNAs in EOC remains unclear. We examined the role of miRNAs in regulating COL11A1 expression. We identified miR-509 and miR-335 as the candidate miRNAs through an online database search. EOC cell treatment with miR-335 mimics abrogated COL11A1 expression and suppressed cell proliferation and invasion, besides increasing the sensitivity of EOC cells to cisplatin. Conversely, treatment with miR-335 inhibitors prompted cell growth/invasiveness and chemoresistance of EOC cells. miR-335 inhibited COL11A1 transcription, thus reducing the invasiveness and chemoresistance of EOC cells via the Ets-1/MMP3 and Akt/c/EBPβ/PDK1 axes, respectively. Furthermore, it did not directly regulate PDK1 but increased PDK1 ubiquitination and degradation through COL11A1 inhibition. In vivo findings highlighted significantly decreased miR-335 mRNA expressions in EOC samples. Furthermore, patients with low miR335 levels were susceptible to advanced-stage cancer, poor response to chemotherapy, and early relapse. This study highlighted the importance of miR-335 in downregulating COL11A1-mediated ovarian tumor progression, chemoresistance, and poor survival and suggested its potential application as a therapeutic target.

Highlights

MicroRNAs are approximately 22-nucleotide-long noncoding RNAs, which are highly conserved among a wide range of species and are generally involved in posttranscriptional gene regulation
We searched for the COL11A1 gene with a binding probability >0.5 in the miRWalk database and identified 596, 1238, and 8874 miRNA target interactions (MTIs) of 3 untranslated region (UTR), 5 UTR, and CDS of COL11A1 gene, respectively (Table S2)
Considering that each miRNA could have more than one binding site of one gene, we identified fewer miRNAs

Summary

Introduction

MicroRNAs (miRNAs) are approximately 22-nucleotide-long noncoding RNAs, which are highly conserved among a wide range of species and are generally involved in posttranscriptional gene regulation. MiRNAs negatively regulate gene expression by binding to the 3 -untranslated region (UTR) of target mRNAs. Often, miRNAs negatively regulate gene expression by binding to the 3 -untranslated region (UTR) of target mRNAs They do not require perfectly complementary target sites and recognize short sites, complementary to their 5 -seed region (nucleotides 2–8 of the miRNAs); one miRNA can regulate numerous mRNAs, and multiple miRNAs can regulate an individual mRNA [1]. These miRNAs supposedly regulate approximately 60% of all human genes and are involved in processes such as development, differentiation, metabolism, proliferation, cell cycle, inflammation, and the regulation of the immune system [2,3,4,5]. Multiple studies have reported the dysregulation of miRNAs in ovarian cancer and suggest their pathobiological importance, such as the regulation of cell proliferation, survival, and stemness, by either the targeted inhibition of tumor suppressor genes or the activation of oncogenes [8,9,10,11,12,13]

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