miR-9-5p Exerts a Dual Role in Cervical Cancer and Targets Transcription Factor TWIST1

Abstract

Squamous cell carcinoma (SCC) and adenocarcinoma (AC) represent the major cervical cancer histotypes. Both histotypes are caused by infection with high-risk HPV (hrHPV) and are associated with deregulated microRNA expression. Histotype-dependent expression has been observed for miR-9-5p, showing increased expression in SCC and low expression in AC. Here, we studied the regulation and functionality of miR-9-5p in cervical SCCs and ACs using cervical tissue samples and hrHPV-containing cell lines. Expression and methylation analysis of cervical tissues revealed that low levels of miR-9-5p in ACs are linked to methylation of its precursor genes, particularly miR-9-1. Stratification of tissue samples and hrHPV-containing cell lines suggested that miR-9-5p depends on both histotype and hrHPV type, with higher expression in SCCs and HPV16-positive cells. MiR-9-5p promoted cell viability and anchorage independence in cervical cancer cell lines SiHa (SCC, HPV16) and CaSki (metastasized SCC, HPV16), while it played a tumor suppressive role in HeLa (AC, HPV18). TWIST1, a transcription factor involved in epithelial-to-mesenchymal transition (EMT), was established as a novel miR-9-5p target. Our results show that miR-9-5p plays a dual role in cervical cancer in a histotype- and hrHPV type-dependent manner. MiR-9-5p mediated silencing of TWIST1 suggests two distinct mechanisms towards EMT in cervical cancer.

Connecting METTL3 and intratumoural CD33+ MDSCs in predicting clinical outcome in cervical cancer

“…In addition to traditional prognostic factors, including age, WHO grade, TNM stage and clinical status, some of the molecular markers could be new predictors of CC prognosis [6,9,10]. However, there are no confirmed molecular markers for tumour progression or prognosis in CC patients.…”

“…In the past decade, researchers worldwide have found that the expression levels of molecular markers in the tumour microenvironment could be an essential factor for cervical cancer (CC) growth and metastasis [ 7 , 8 ]. In addition to traditional prognostic factors, including age, WHO grade, TNM stage and clinical status, some of the molecular markers could be new predictors of CC prognosis [ 6 , 9 , 10 ]. However, there are no confirmed molecular markers for tumour progression or prognosis in CC patients.…”

<p><em>MiR-139-5p-ZEB1</em> is a Molecular Regulator of Growth, Invasion, and Epithelial-to-Mesenchymal Transition of Cervical Cancer</p>

“…20,21 At present, CC is intractable, which is mainly manifested in drug resistance and lack of effective treatment strategies for advanced or recurrent CC. 22 A large body of evidence has verified that the abnormal dysregulation of miRNA is linked to tumor progression, 23,24 so analyzing the molecular mechanism of miRNA in CC is of great value for improving treatment schemes, prevention, and management of CC. According to clinical analysis, miR-139-5p was expressed at low levels in cancerous tissues and serum of patients with CC, while ZEB1 was expressed at high levels in them, and both serum miR-139-5p and ZEB1 had relatively high diagnostic value (AUC=0.923 and 0.890, respectively).…”

Connecting METTL3 and intratumoural CD33+ MDSCs in predicting clinical outcome in cervical cancer

“…In the past decade, researchers worldwide have found that the expression levels of molecular markers in the tumour microenvironment could be an essential factor for cervical cancer (CC) growth and metastasis (7,8). In addition to traditional prognostic factors, including age, WHO grade, TNM stage and clinical status, some of the molecular markers could be new predictors of CC prognosis (6,9,10). However, there are no con rmed molecular markers for tumour progression or prognosis in CC patients.…”