A DHX9-lncRNA-MDM2 interaction regulates cell invasion and angiogenesis of cervical cancer

Xiangya Ding,Xuemei Jia,Cong Wang,Shou-Jiang Gao,Jingyun Xu,Chun Lu

doi:10.1038/s41418-018-0242-0

Abstract

Cervical cancer (CC) is the third most common carcinoma and the fourth leading cause of cancer-associated mortality in women. Here, we report that MDM2-DHX9 interaction mediates CC motility and angiogenesis in a long noncoding RNA-dependent fashion. A long noncoding RNA, named lnc-CCDST, is significantly downregulated in CC tissues, and binds to pro-oncogenic DHX9. DHX9 is upregulated in CC tissue, and promotes CC cell motility and angiogenesis. The lnc-CCDST and DHX9 interaction promotes DHX9 degradation through the ubiquitin proteasome pathway. Furthermore, DHX9 bound to E3 ubiquitin ligase MDM2, and this interaction is enhanced by lnc-CCDST. Thus, lnc-CCDST promotes DHX9 degradation by serving as a scaffold to facilitate the formation of MDM2 and DHX9 complexes. Moreover, HPV oncogenes E6 and E7 abolish the expression of lnc-CCDST resulting in the increase of DHX9. Our results have revealed a novel mechanism by which high-risk HPVs promote motility and angiogenesis of CC by inhibiting expression of lnc-CCDST to disrupt MDM2 and DHX9 interaction, and DHX9 degradation, and identified a potential therapeutic target for CC.

Highlights

The incidence and mortality rate of cervical cancer (CC) have continued to decline in recent years, CC remains as the third most common carcinoma and the fourth leading cause of cancer-associated mortality in females worldwide
We report an important role of a Long noncoding RNAs (lncRNAs) named cervical cancer DExH-box helicase 9 (DHX9) suppressive transcript, which is significantly downregulated in CC tissues
The screening identified eight candidate lncRNAs (Fig. 1a) that differed significantly between cancer and paired normal tissues. Some of these lncRNAs have previously been investigated in other types of cancer, there is no report in cancer on lncRNA ENST00000429352, which we named lnc-CCDST

Summary

Introduction

The incidence and mortality rate of cervical cancer (CC) have continued to decline in recent years, CC remains as the third most common carcinoma and the fourth leading cause of cancer-associated mortality in females worldwide. According to the WHO datum, 528,000 new cases of CC were diagnosed and 266,000 patients died of the cancer in 2012. Early screening programs have reduced the mortality rates of CC patients, tumor metastasis continues to occur and negatively impact survival even for some diagnosed in early stage [2]. Human papillomavirus (HPV) infection causes more than 90% of CC cases [3]. High-risk HPV 16 and 18 are the causes of 75% of CC cases with the remaining cases associated with other high-risk HPVs [3]. E6 and E7 have evolved numerous strategies to alter cell cycle and apoptosis control, and evade host immuno-surveillance while maintain viral persistence

Methods

Results

Conclusion