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Mol Cancer. 2019 Dec 2;18(1):174. doi: 10.1186/s12943-019-1105-0.

LncRNA LINRIS stabilizes IGF2BP2 and promotes the aerobic glycolysis in colorectal cancer.

Wang Y1,2, Lu JH1,3, Wu QN1,4, Jin Y1,2, Wang DS1,2, Chen YX1,2, Liu J1,2, Luo XJ1,2, Meng Q1,2, Pu HY1, Wang YN1, Hu PS1, Liu ZX1, Zeng ZL1, Zhao Q1, Deng R1, Zhu XF1, Ju HQ5,6, Xu RH7,8,9.

Author information

1
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
2
Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.
3
Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
4
Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China.
5
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China. juhq@sysucc.org.cn.
6
Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, China. juhq@sysucc.org.cn.
7
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China. xurh@sysucc.org.cn.
8
Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China. xurh@sysucc.org.cn.
9
Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, China. xurh@sysucc.org.cn.

Abstract

BACKGROUND:

Long noncoding RNAs (lncRNAs) play nonnegligible roles in the epigenetic regulation of cancer cells. This study aimed to identify a specific lncRNA that promotes the colorectal cancer (CRC) progression and could be a potential therapeutic target.

METHODS:

We screened highly expressed lncRNAs in human CRC samples compared with their matched adjacent normal tissues. The proteins that interact with LINRIS (Long Intergenic Noncoding RNA for IGF2BP2 Stability) were confirmed by RNA pull-down and RNA immunoprecipitation (RIP) assays. The proliferation and metabolic alteration of CRC cells with LINRIS inhibited were tested in vitro and in vivo.

RESULTS:

LINRIS was upregulated in CRC tissues from patients with poor overall survival (OS), and LINRIS inhibition led to the impaired CRC cell line growth. Moreover, knockdown of LINRIS resulted in a decreased level of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), a newly found N6-methyladenosine (m6A) 'reader'. LINRIS blocked K139 ubiquitination of IGF2BP2, maintaining its stability. This process prevented the degradation of IGF2BP2 through the autophagy-lysosome pathway (ALP). Therefore, knockdown of LINRIS attenuated the downstream effects of IGF2BP2, especially MYC-mediated glycolysis in CRC cells. In addition, the transcription of LINRIS could be inhibited by GATA3 in CRC cells. In vivo experiments showed that the inhibition of LINRIS suppressed the proliferation of tumors in orthotopic models and in patient-derived xenograft (PDX) models.

CONCLUSION:

LINRIS is an independent prognostic biomarker for CRC. The LINRIS-IGF2BP2-MYC axis promotes the progression of CRC and is a promising therapeutic target.

KEYWORDS:

Autophagy; CRC; IGF2BP2; LINRIS; MYC

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