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IntegrinB5 upregulated by HER2 in gastric cancer: a promising biomarker for liver metastasis.

ABSTRACT: Background:Liver is the most frequent metastatic site of gastric cancer (GC), especially in patients with HER2 positive GC. Exosomal integrin ?v?5 has been shown to promote liver metastasis (LM), and the cross talk between integrins and HER2 during breast cancer metastasis has been reported. However, whether there's an association between HER2 and integrin ?v?5 (ITGAvB5), and whether their association has predictive value in GC liver metastasis (GCLM) remains unknown. Methods:The association between ITG?5 and HER2 were accessed by RT-PCR, western blot and ELISA. We tested the function of ITG?5 on HER2 positive GC cells using Transwell assays and scratch assays. Besides, we detect ITG?5 expression in tumor tissue of GC patients and exosomes derived from advanced GC to analyze the association between HER2 and LM. Results:In our study, we found that ITG?5, rather than ITGAV, was highly upregulated by HER2 through PI3K-AKT pathways in HER2 positive GC. Overexpression of ITG?5 promoted the migration and invasion of HER2 positive GC cells in vitro. ITG?5 was found to be an independent prognostic factor for GC. Besides, ITG?5 level was only associated with LM. Detection of exosomal ITG?5 and HER2 in the serum of GC patients revealed that exosomal ITG?5 and HER2 levels are in accordance with that in tissue, and exosomal ITG?5 level was higher in GCLM than other metastasis. Conclusions:Our study demonstrated ITG?5 is regulated and functions in accordance with HER2 in promoting GCLM. Exosomal ITG?5 levels might be a potential liquid biopsy biomarker for GCLM.

SUBMITTER: Li Q

PROVIDER: S-EPMC7210205 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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IntegrinB5 upregulated by HER2 in gastric cancer: a promising biomarker for liver metastasis.

Li Qian Q Peng Ke K Chen Erbao E Jiang Huiqin H Wang Yan Y Yu Shan S Li Wei W Yu Yiyi Y Liu Tianshu T

Annals of translational medicine 20200401 7

<h4>Background</h4>Liver is the most frequent metastatic site of gastric cancer (GC), especially in patients with HER2 positive GC. Exosomal integrin αvβ5 has been shown to promote liver metastasis (LM), and the cross talk between integrins and HER2 during breast cancer metastasis has been reported. However, whether there's an association between HER2 and integrin αvβ5 (ITGAvB5), and whether their association has predictive value in GC liver metastasis (GCLM) remains unknown.<h4>Methods</h4>The ...[more]

PMID: 32395495

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Project description:Cullin 4B (CUL4B), a scaffold protein that assembles CRL4B ubiquitin ligase complexes, has been reported to be overexpressed in several types of solid tumors and contributes to epigenetic silencing of tumor suppressor. However, its clinical significance and the molecular mechanisms underlying its regulation in gastric cancer (GC) remain largely unknown. Here, we showed that CUL4B was elevated in GC tissues and its overexpression was positively correlated with poor prognosis and lymph node metastasis. CUL4B knockdown in GC cells decreased proliferation, mesenchymal transition and invasion in vitro, as well as tumor growth and metastasis in nude mice, and CUL4B overexpression induced the opposite results. Further studies showed that miR-101 could inhibit CUL4B expression by directly targeting its 3’-UTR and they were inversely correlated in clinical GC specimens. Notably, a positive relationship between CUL4B and HER2 was found in GC clinical specimens, GC cells and GC xenograft tumors. Through bioinformatics analysis of miRNA-seq data and target prediction, we nominated miR-125a as a direct target of CUL4B. ChIP assays demonstrated that CUL4B directly repressed miR-125a expression by physically binding to its promoter. In addition, we confirmed miR-125a is the target of HER2. Consequently, we demonstrated that CUL4B can up-regulate HER2 expression through repressing miR-125a. Most importantly, silencing of HER2 by Herceptin or siRNA partially reversed CUL4B-induced epithelial-to-mesenchymal transition (EMT), cell invasion and metastasis in vitro and in vivo. These findings define a CUL4B-miR-125a-HER2 regulatory mechanism shed light on CUL4B oncogenic mechanisms and reveals promising therapeutic targets for progressive GC. CUL4B proteins are frequently upregulated in human cancer, yet little is known about the underlying molecular mechanisms of CUL4B induced gastric cancer(GC) carcigenesis.Here, we uncover the critical role of CUL4B in gastric cancer growth and metastasis through the regulation of HER2 expression.CUL4B contributes to GC invasion and metastasis by transcriptional repression of HER2 targeting miR-125a, which provide a new insight into how CUL4B regulates GC progression and metastasis.

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IntegrinB5 upregulated by HER2 in gastric cancer: a promising biomarker for liver metastasis.

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IntegrinB5 upregulated by HER2 in gastric cancer: a promising biomarker for liver metastasis.

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