A novel miRNA identified in GRSF1 complex drives the metastasis via the PIK3R3/AKT/NF-\u03baB and TIMP3/MMP9 pathways in cervical cancer cells

Qi Sun,Shixing Wang,Xu Wang,Hua Tang,Pu Li,Lu Sun,Min Liu,Zhen Yang

doi:10.1038/s41419-019-1841-5

Abstract

microRNAs (miRNAs) play an important role in carcinogenesis. Typically, miRNAs downregulate the target expression by binding to the 3′ UTR of mRNAs. However, recent studies have demonstrated that miRNAs can upregulate target gene expression, but its mechanism is not fully understood. We previously found that G-rich RNA sequence binding protein (GRSF1) mediates upregulation of miR-346 on hTERT gene. To explore whether GRSF1 mediate other miRNA’s upregulation on their target genes, we obtained profile of GRSF1-bound miRNAs by Flag-GRSF1-RIP-deep sequencing and found 12 novel miRNAs, named miR-G. In this study, we focused on miR-G-10, which is highly expressed in cervical cancer tissues and cell lines and serum from patients with metastatic cervical cancer. miR-G-10 in cervical cancer cells significantly promoted migration/invasion and anoikis resistance in vitro and lung metastasis in vivo. Furthermore, miR-G-10 bound to the 3′ UTR of PIK3R3 and upregulated its expression to activate the AKT/NF-κB signal pathway in a GRSF1-dependent manner, whereas miR-G-10 suppressed TIMP3 in the AGO2 complex to modulate the MMP9 signaling pathway in cervical cancer cells. Taken together, our findings may provide a new insight into the upregulation mechanism mediated by miRNAs and a potential biomarker for cervical cancer.

Highlights

Cervical cancer (CC) is the fourth most common malignancy and a crucial cause of cancer-associated mortality in women[1,2]
We demonstrated that phosphatidylinositol 3-kinase regulatory subunit gamma (PIK3R3) and tissue inhibitors of metalloproteinase 3 (TIMP3) are direct targets of miR-G-10 and identify them as crucial regulators of the AKT/NFκB and MMP9 pathways, respectively
We found that the precursor of miR-G-10 located in the Chromosome 5 (136129333, 136129440), which is the noncoding region of human SMAD family member 5 (SMAD5)

Summary

Introduction

Cervical cancer (CC) is the fourth most common malignancy and a crucial cause of cancer-associated mortality in women[1,2]. Enhanced pathological examination of cervical cancer tissue and improved inchoate diagnosis have significantly reduced the morbidity and mortality of this disease in the past decades[4,5]. The certain molecular mechanisms of cervical carcinogenesis have. MiR-369-3p promotes TNFα translation through AU-rich elements (AREs)[13], miR-4903p upregulates endoplasmic reticulum–Golgi intermediate compartment 3 (ERGIC3) in human hepatocellular carcinoma cells[14]. We elucidated that G-rich RNA sequence binding protein (GRSF1) mediates miR-346 to enhance expression of human telomerase reverse transcriptase (hTERT) in cervical cancer cells. MiR-23a promotes IKKα expression to contribute to the malignancy of epithelial ovarian cancer cells[16].

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