The lncRNA SEMA3B-AS1/HMGB1/FBXW7 Axis Mediates the Peritoneal Metastasis of Gastric Cancer by Regulating BGN Protein Ubiquitination.

Guoquan Huang,Rongzhang Dou,Bin Xiong,Chaogang Yang,Jialin Song,Haitao Wu,Shuyi Wang,Sihao Huang,Qiuming He,Zhenxian Xiang,Laura Bravo

doi:10.1155/2022/5055684

Abstract

Peritoneal metastasis (PM) is one of the main causes of a poor prognosis in patients with advanced gastric cancer (GC). lncRNAs have been confirmed to play a very crucial role in the occurrence, development, and metastasis of many human cancers, including gastric cancer. However, the mechanism of lncRNA in PM of GC is rarely studied. We explored the mechanism of PM of GC through lncRNA gene sequencing and protein profiling analysis to detect PM-associated lncRNAs and proteins. A quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed to identify the mRNA expression of SEMA3B-AS1 and BGN in GC tissues and adjacent normal tissues. The biological function of SEMA3B-AS1 in the PM of GC was identified through gain- and loss-of-function assays. Chromatin isolation by RNA purification (ChIRP), RNA immunoprecipitation (RIP), RNA pull-down, luciferase reporter, and coimmunoprecipitation (co-IP) assays was carried out to demonstrate the potential mechanism between SEMA3B-AS1 and its downstream genes, including HMGB1, FBXW7, and BGN. Finally, the biological function of SEMA3B-AS1 was demonstrated in animal experiments. The mRNA expression level of SEMA3B-AS1 was downregulated in GC and PM tissues compared to normal stomach tissues; however, BGN was highly expressed at the mRNA level. SEMA3B-AS1 was closely related to PM and the overall survival (OS) of GC patients. Functionally, the overexpression of SEMA3B-AS1 was related to GC progression, PM, and prognosis. Mechanistically, SEMA3B-AS1 could combine with HMGB1 to regulate the transcription of FBXW7, thus facilitating the ubiquitination of BGN. In conclusion, our study demonstrated that the SEMA3B-AS1/HMGB1/FBXW7 axis plays an inhibitory role in the PM of GC by regulating BGN protein ubiquitination. It also provides a new biological marker for the diagnosis and treatment of the PM of GC.

Highlights

Gastric cancer (GC) is one of the leading causes of cancerrelated death worldwide [1, 2]
According to the Long noncoding RNAs (lncRNAs) sequencing results of our research group, we found that SEMA3B-AS1 expression was decreased in peritoneal metastasis (PM) tissues compared to primary lesion tissues (Figure 1(a))
We verified the SEMA3B-AS1 mRNA expression level in five gastric cancer cell lines (AGS, HGC-27, MGC-803, MKN45, and SGC-7901) and a normal stomach mucosal cell line (GES-1) through quantitative reverse transcription polymerase chain reaction (qRT-PCR) assay, and it was demonstrated that SEMA3B-AS1 expression was decreased in GC cells compared to GES-1 cells (Figure 1(b))

Summary

Introduction

Gastric cancer (GC) is one of the leading causes of cancerrelated death worldwide [1, 2]. Great progress has been made in the treatment of GC, the prognosis of the peritoneal metastasis (PM) of GC remains poor [3, 4]. The mechanism of the PM of GC remains unclear, and there is a lack of effective means for the early diagnosis and treatment of PM. It is urgent for us to further explore the molecular biological mechanism of the PM of GC and find new diagnostic and therapeutic markers. Long noncoding RNAs (lncRNAs) play a vital role in the occurrence, development, invasion, and metastasis of cancer. LncRNAs are more than 200 nt in length and have a conserved secondary structure, and most of them do not have Long noncoding RNAs (lncRNAs) play a vital role in the occurrence, development, invasion, and metastasis of cancer. lncRNAs are more than 200 nt in length and have a conserved secondary structure, and most of them do not have

Methods

Results

Discussion

Conclusion