MALAT1-miR-101-SOX9 feedback loop modulates the chemo-resistance of lung cancer cell to DDP via Wnt signaling pathway.

Wei Chen,Zongren Wan,Li Zhang,Lixin Wang,Liang Yu,Wei Zhao,Yongqing Hong,Jipeng Wang

doi:10.18632/oncotarget.21693

Abstract

Cisplatin (DDP)-based chemotherapy is a standard strategy for lung cancer, while chemoresistance remains a major therapeutic challenge. Recent evidence highlights the crucial regulatory roles of long non-coding RNAs (lncRNA) in tumor biology. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has important roles in regulating the proliferation, invasion and migration of lung cancer cell. High MALAT1 expression in lung cancer was related to poorer clinicopathologic features in this study. MALAT1 knockdown alone was sufficient to amplify DDP-induced repression of cell viability. MALAT1 knockdown could also sensitized DDP-resistant lung cancer cells (A549/DDP and H1299/DDP) to DDP. Further assays indicated that MALAT1 acted as a competing endogenous RNA to upregulate SOX9 expression by sponging miR-101 in DDP-resistant cancer cells, through Wnt signaling pathway. Moreover, SOX9 could bind to the promoter of MALAT1 to activate its transcription. Taken together, MALAT1, miR-101 and SOX9 form a feedback loop to enhance the chemo-resistance of lung cancer cell to DDP; this MALAT1-miR-101-SOX9 feedback loop plays an important role in the chemo-resistance of lung cancer cell to DDP and may serve as a potential target for cancer treatment.

Highlights

Lung cancer is the most common cause of global cancer-related death. 1.8 million people are diagnosed with lung cancer each year, and 1.6 million people die from the disease. 5-year survival rates range from 4-17% depending on stage and regional differences [1, 2]
The results indicated that patients with higher Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) expression had a significantly poorer prognosis compared www.impactjournals.com/oncotarget
Accumulating evidence confirms that long non-coding RNAs (lncRNA) can affect the sensitivity of cancer cells to chemotherapy

Summary

Introduction

Lung cancer is the most common cause of global cancer-related death. 1.8 million people are diagnosed with lung cancer each year, and 1.6 million people die from the disease. 5-year survival rates range from 4-17% depending on stage and regional differences [1, 2]. DDP is the most common used agent in lung cancer therapy, but the chemo-resistance of lung cancer cells still remains a huge challenge. To identify biomarkers that promote early diagnosis and allow personalized therapy for patients, and to figure out the underlying mechanism of the lung cancer cell chemo-resistance has become an urgent need [2, 3]. The roles of small non-coding RNAs such as microRNAs (miRNAs) in gene regulation and cell function have been extensively studied in numerous cancers [5]. MiRNAs have been regarded as essential regulators in resistance to lung cancer treatments [6], including Cisplatin (DDP)-based chemotherapy [7]. In addition to miRNAs, recent studies have shown that long non-coding RNAs (lncRNAs) play an important role in normal development and diseases, including cancer [8]. In addition to cancer cell proliferation, invasion and www.impactjournals.com/oncotarget migration, the roles of lncRNAs in cancer cell chemoresistance have been frequently reported [9,10,11]

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