MiR-106a Regulates Cell Proliferation and Autophagy by Targeting LKB1 in HPV-16-Associated Cervical Cancer.

Xiujie Cui,Xiao Wang,Hanxiang Chen,Weiming Zhao,Jihui Jia,Xiaoqing Zhou

doi:10.1158/1541-7786.mcr-19-1114

Abstract

miR-106a is aberrantly regulated in various tumors and plays an important role in carcinogenesis. However, the biological role and molecular mechanism by which miR-106a contributes to cervical squamous cell carcinoma (CSCC) remains elusive. In this study, we verified that miR-106a was elevated in both human papilloma virus (HPV) 16-positive CSCC tissues and cell lines. ROC curve analysis showed that miR-106a could well distinguish HPV-16-positive CSCC tissues from normal cervical squamous epithelium tissues. High expression of miR-106a was associated with malignant clinicopathologic parameters in CSCC tissues. Exogenous expression of miR-106a greatly promoted cervical cancer cell proliferation while attenuated autophagy. Furthermore, a novel target of miR-106a, liver kinase B1 (LKB1), a proven tumor suppressor in cervical cancer was verified. Here we confirmed LKB1 was negatively correlated with malignant clinicopathologic parameters in CSCC tissues. Overexpression of LKB1 neutralized the effect of miR-106a on proliferation and autophagy in cervical cancer cell lines. In addition, the role of miR-106a in cell proliferation and autophagy was via LKB1 and its downstream pathway AMP-activated protein kinase-mammalian target of rapamycin. Of note, miR-106a was upregulated by HPV-16 E7 protein. The function of HPV-16 E7 to cell proliferation was suppressed when knockdown miR-106a in HPV-16 E7-expressing cells. IMPLICATIONS: Our study highlights the tumorigenic role and regulatory mechanism of miR-106a in CSCC. miR-106a may be a potential therapeutic target in HPV-associated cervical cancer.

Highlights

Despite widespread screening for cervical cancer and major advances in the development of vaccines, cervical cancer occurs frequently in women worldwide, with high mortality in developing countries [1, 2]
In the 91 cases of cervical squamous cell carcinoma (CSCC), 72 samples tested positive for human papillomavirus (HPV)-16 (79.1%). miR-106a expression was significantly upregulated in HPV-16–positive CSCC tissues as compared with HPV-negative normal cervical squamous epithelium tissue (P < 0.001; Fig. 1A)
We showed that miR-106a plays an oncogenic role in HPV-16–related cervical cancer. miR-106a was substantially upregulated in HPV-16–positive cervical cancer tissues, and high expression of miR-106a was associated with malignant clinicopathologic features, such as larger tumor size, poor differentiation, and lymph node metastasis of HPV-16–positive cervical cancer

Summary

Introduction

Despite widespread screening for cervical cancer and major advances in the development of vaccines, cervical cancer occurs frequently in women worldwide, with high mortality in developing countries [1, 2]. Studies of the pathogenesis of cervical cancer have confirmed that persistent infection with human papillomavirus (HPV), types 16 and 18, plays a central aetiologic role in tumorigenesis of cervical cancer [3]. Additional factors, such as changes in levels of cellular proteins that are crucial regulators in certain molecular signaling pathways are involved in the progression of HPV-infected lesions to cancer [4]. The impact of abnormal miRNA expression on cervical carcinogenesis has been a growing concern for researchers [5, 6].

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Results

Conclusion