Chemotherapy-mediated miR-29b expression inhibits the invasion and angiogenesis of cervical cancer.

Zhongzu Zhang,Ying Lin,Qin Zhou,Tangshu Luo,Xiaojing Zhang,Zhenghua Xiao,Yunyun Li

doi:10.18632/oncotarget.14738

Abstract

Radiotherapy combined with platinum-based chemotherapy is the standard-of-care of locally advanced cervical cancer (CC) patients, while nearly 50% of patients do not respond to standard chemotherapy. Thus, identification of relative molecules participated in chemotherapy might provide new insights in the treatment of CC. In this study, we found a cohort of miRNAs were dysregulated upon treatment with cisplatin, among of which miR-29b was the most upregulated one. We further detected its expression in CC tissues, and found that miR-29b was significantly suppressed in CC and its precancerous lesions, HSIL tissues, and was negatively related with tumor invasion. However, upon treatment with cisplatin, the expression of miR-29b was significantly up-regulated. The biological function assays showed that overexpression of miR-29b suppressed the invasion, EMT procedure and angiogenesis of cervical cancer cells in vitro and inhibited tumor growth and neovascularization in vivo through targeting STAT3 signal pathway. While, inhibition of miR-29b could prevent the cisplatin-induced epithelial features, cell movement and angiogenesis of CC cells, which means miR-29b/STAT3 axis participates in the chemotherapy of cisplatin in CC. Collectively, our data suggest that chemotherapy-mediated miR-29b expression participates in the initiation and progression of cervical cancer through suppressing the proliferation, EMT procedure and angiogenesis of cervical cancer cells by targeting STAT3 signal pathway.

Highlights

Cervical cancer (CC) is the second most common cancer in women worldwide
Understanding the putative mechanisms involved in chemotherapy of cisplatin might provide new insights in the treatment of cervical cancer, Figure 2: miR-29b functions as a tumor suppressor in cervical cancer. (A) RT-PCR was performed to detect the expression of miR-29b in cervical cancer cells upon transfection with miR-29b mimic; (B) Cell Counting Kit8 (CCK-8) assays were performed to analyze the effect of miR29b on cell proliferation of both cell lines
We reported a cohort of miRNAs dysregulated upon treatment with cisplatin, from which miR-29b was validated to be correlated with cisplatin chemotherapy, and performed as a tumor suppressor through suppressing the invasion and angiogenesis of cervical cancer cells

Summary

Introduction

Cervical cancer (CC) is the second most common cancer in women worldwide. Despite the introduction of vaccines to high-risk human papilloma viral (hrHPV) strains, CC remains a major source of cancer related death, in under-developed countries [1, 2]. The intrinsic molecular mechanisms of chemotherapeutic drugs used for cervical cancer treatment are not well established. The pivotal role of miRNAs in the chemotherapy of variety www.impactjournals.com/oncotarget of cancers have been widely reported, such as miR-135a promotes the gastric cancer resistance to oxaliplatin through suppressing the E2F1/Sp1/DAPK2 pathway signaling [7]; overexpression of miR-126 could increase chemosensitivity in drug-resistant gastric cancer cells by targeting EZH2 [8]. Through comparing the miRNAs profile between the non-response and complete-response patients upon chemotherapy with cisplatin, Abraham et al identified a molecular signature consisting of seven validated miRNAs [9], while whether these miRNAs are all involved in the chemotherapy of cisplatin in cervical cancer, and the intrinsic mechanisms involved are less known

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Conclusion