LncRNA RPPH1 promotes colorectal cancer metastasis by interacting with TUBB3 and by promoting exosomes-mediated macrophage M2 polarization

Zhen-Xing Liang,Xian-Rui Wu,Dan Xie,Chi Zhou,Hua-Shan Liu,Xiao-Wen He,Feng-Wei Wang,Tuo Hu,Xiao-Jian Wu,Ping Lan,Li Xiong

doi:10.1038/s41419-019-2077-0

Abstract

Metastasis is a well-known poor prognostic factor in cancer. However, the mechanisms how long non-coding RNAs (lncRNAs) regulate metastasis in colorectal cancer (CRC) remain largely unknown. Besides, tumor-associated macrophages (TAMs) play an important role in tumor progression, yet the contribution of lncRNA-mediated crosstalk between TAMs and CRC cells to tumor progression is not well understood. In this study, we report that lncRNA RPPH1 was significantly upregulated in CRC tissues, and the RPPH1 overexpression was associated with advanced TNM stages and poor prognosis. RPPH1 was found to promote CRC metastasis in vitro and in vivo. Mechanistically, RPPH1 induced epithelial–mesenchymal transition (EMT) of CRC cells via interacting with β-III tubulin (TUBB3) to prevent its ubiquitination. Furthermore, CRC cell-derived exosomes transported RPPH1 into macrophages which mediate macrophage M2 polarization, thereby in turn promoting metastasis and proliferation of CRC cells. In addition, exosomal RPPH1 levels in blood plasma turned out to be higher in treatment-naive CRC patients but lower after tumor resection. Compared to CEA and CA199, exosomal RPPH1 in CRC plasma displayed a better diagnostic value (AUC = 0.86). Collectively, RPPH1 serves as a potential therapeutic and diagnostic target in CRC.

Highlights

Colorectal cancer (CRC) is one of the most prevalent cancers in the world[1]
To identify Long non-coding RNAs (lncRNAs) which contribute to metastasis, next-generation sequencing (NGS) was performed on paired CRC samples and normal adjacent tissues (NATs) from seven CRC patients with liver metastasis
Metastasis of CRC is a major contributing of poor prognosis[30]

Summary

Introduction

Colorectal cancer (CRC) is one of the most prevalent cancers in the world[1]. It accounted for 8% of cancer incidence and 8% of the cancer-related deaths in 20182. The poor prognosis is largely due to the distant metastasis, which accounts for about 90% of cancer-related deaths[3,4]. Many studies have shown that lncRNAs participate in a series of biological processes, including epigenetic, transcriptional, and post-transcriptional levels, as well as the initiation and progression of cancers[6,7,8,9]. Emerging evidence suggests that lncRNAs participate in every stage of metastasis from cell migration to distantorgan colonization[10].

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Results

Conclusion