LINC01133 promotes hepatocellular carcinoma progression by sponging miR‐199a‐5p and activating annexin A2

Abstract

Background Long noncoding RNAs (lncRNAs) are functionally associated with cancer development and progression. Although gene copy number variation (CNV) is common in hepatocellular carcinoma (HCC), it is not known how CNV in lncRNAs affects HCC progression and recurrence. We aimed to identify a CNV‐related lncRNA involved in HCC progression and recurrence and illustrate its underlying mechanisms and prognostic value. Methods We analyzed the whole genome sequencing (WGS) data of matched cancerous and noncancerous liver samples from 49 patients with HCC to identify lncRNAs with CNV. The results were validated in another cohort of 238 paired HCC and nontumor samples by TaqMan copy number assay. We preformed Kaplan‐Meier analysis and log‐rank test to identify lncRNA CNV with prognostic value. We conducted loss‐ and gain‐of‐function studies to explore the biological functions of LINC01133 in vitro and in vivo. The competing endogenous RNAs (ceRNAs) mechanism was clarified by microRNA sequencing (miR‐seq), quantitative real‐time PCR (qRT‐PCR), western blot, and dual‐luciferase reporter assays. We confirmed the binding mechanism between lncRNA and protein by RNA pull‐down, RNA immunoprecipitation, qRT‐PCR, and western blot analyses. Results Genomic copy numbers of LINC01133 were increased in HCC, which were positively related with the elevated expression of LINC01133. Increased copy number of LINC01133 predicted the poor prognosis in HCC patients. LINC01133 overexpression in HCC cells promoted proliferation and aggressive phenotypes in vitro, and facilitated tumor growth and lung metastasis in vivo, whereas LINC01133 knockdown had the opposite effects. LINC01133 sponged miR‐199a‐5p, resulting in enhanced expression of SNAI1, which induced epithelial‐to‐mesenchymal transition (EMT) in HCC cells. In addition, LINC01133 interacted with Annexin A2 (ANXA2) to activate the ANXA2/STAT3 signaling pathway. Conclusions LINC01133 promotes HCC progression by sponging miR‐199a‐5p and interacting with ANXA2. LINC01133 CNV gain is predictive of poor prognosis in patients with HCC.

The Mechanism Underlying the ncRNA Dysregulation Pattern in Hepatocellular Carcinoma and Its Tumor Microenvironment

“…The whole-genome sequencing data of 49 Chinese HCC patients showed that lncRNAs were amplified in HCC tumor tissues mainly located on chromosomes 1q, 8q, 17q, and 20q, while lncRNAs deleted in the tumor tissues were mostly located on chromosomes 4q, 9q, 13q, and 16q. TaqMan copy number assay of HCC tumors and normal liver tissues from 238 patients further confirmed that lncRNAs with copy number gain in >50% of HCC samples were all upregulated in tumor tissues (18). In another study, to explore the association between HCC metastasis and lncRNAs, Yang et al (19) identified 917 recurrently deregulated lncRNAs, and 147 of these recurrently deregulated lncRNAs were found in deleted regions.…”

The Role of N6-Methyladenosine-associated lncRNAs in Immune Microenvironment and Prognosis of Colorectal Cancer

“…Current studies have indicated that lncRNAs play important roles in predicting the outcome and prognosis of various cancers. For instance, Dan Yin, et al 21 reported that overexpression of LINC01133 was related to the poor prognosis in patients with hepatocellular carcinoma. Shujun Feng, et al 22 reported that lncRNA-CTS was aberrantly expressed in gastric cancer tissues, and the upregulation of CTS was closely associated with tumor volume, tumor histology, lymph node metastasis and the poor prognosis.…”

Expression changes of serum LINC00941 and LINC00514 in HBV infection‐related liver diseases and their potential application values

“… 21 Yin et al found that LINC01133 expression in HCC tissues was elevated, and can predict the poor prognosis of HCC patients; in‐vitro studies showed that overexpression of LINC01133 can promote the proliferation and aggressive phenotype of HCC cells, and promote tumor growth and lung metastasis in vivo, while knockdown LINC01133 had the opposite effect. 22 In addition, studies have also reported that lncRNA plays an important role in the chemotherapy resistance of HCC. The study of Ma et al found that the expression of LINC01134 was upregulated after treatment with oxaliplatin (OXA), and the higher expression of LINC01134 was related to the poor treatment effect of OXA; mechanistic studies have shown that the LINC01134/SP1/p62 axis modulated OXA resistance by changing cell viability, apoptosis and mitochondrial homeostasis in vitro and in vivo, suggesting that the LINC01134/SP1/p62 axis may be a promising strategy to overcome OXA chemotherapy resistance.…”