{"title":"Overexpression of SHANK2 contributes malignant outcomes as a Hippo pathway regulator in gastric cancer.","authors":"Hiroshi Arakawa, Shuhei Komatsu, Jun Kiuchi, Taisuke Imamura, Keiji Nishibeppu, Hajime Kamiya, Yusuke Takashima, Ryo Ishida, Satoshi Hamada, Masateru Yamauchi, Takuma Ohashi, Hiroki Shimizu, Tomohiro Arita, Hirotaka Konishi, Atsushi Shiozaki, Takeshi Kubota, Hitoshi Fujiwara, Hitoshi Tsuda, Eigo Otsuji","doi":"10.62347/NZMO2658","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Recent studies identified that SH3 and multiple ankyrin repeat domains 2 (SHANK2) is located in a gene-amplified region 11q13 of various human cancers, and has oncogenic functions as a Hippo pathway suppressor in hepatocellular carcinoma. In this study, we tested whether SHANK2 acts as a cancer-promoting gene through its activation or overexpression in gastric cancer (GC).</p><p><strong>Materials and methods: </strong>We analyzed 5 GC cell lines and 172 primary tumor samples of GC, which were curatively resected in our hospital.</p><p><strong>Results: </strong>Overexpression of SHANK2 protein was frequently detected in GC cell lines (4/5 cell lines, 80%). Knockdown of SHANK2 inhibited cell proliferation, migration and invasion of GC cells in a <i>TP53</i> mutation-independent manner, and induced the overexpression of the Hippo pathway genes. Fluorescent immunostaining showed that overexpression of SHANK2 in cytoplasm was inversely correlated with Yes1-associated transcriptional regulator (YAP) expression, suggesting that SHANK2 may play a role in suppressing the Hippo pathway in GC. In primary GC samples, both overexpression of SHANK2 in cytoplasm and low expression of SHANK2 in nucleus, which are defined as high SHANK2 index, correlated with more aggressive venous invasion, advanced tumor and nodal stage. Patients with high SHANK2 index tumors had a lower overall survival rate than those with non-expressing tumors. Multivariate analysis demonstrated that high SHANK2 index was independently associated with poor outcomes.</p><p><strong>Conclusions: </strong>These findings suggest that SHANK2 plays a crucial role in tumor malignant potential through the Hippo pathway suppression and highlight its usefulness as a prognostic factor and potential therapeutic target in GC.</p>","PeriodicalId":7437,"journal":{"name":"American journal of cancer research","volume":"15 1","pages":"363-374"},"PeriodicalIF":3.6000,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11815361/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"American journal of cancer research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.62347/NZMO2658","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Background: Recent studies identified that SH3 and multiple ankyrin repeat domains 2 (SHANK2) is located in a gene-amplified region 11q13 of various human cancers, and has oncogenic functions as a Hippo pathway suppressor in hepatocellular carcinoma. In this study, we tested whether SHANK2 acts as a cancer-promoting gene through its activation or overexpression in gastric cancer (GC).
Materials and methods: We analyzed 5 GC cell lines and 172 primary tumor samples of GC, which were curatively resected in our hospital.
Results: Overexpression of SHANK2 protein was frequently detected in GC cell lines (4/5 cell lines, 80%). Knockdown of SHANK2 inhibited cell proliferation, migration and invasion of GC cells in a TP53 mutation-independent manner, and induced the overexpression of the Hippo pathway genes. Fluorescent immunostaining showed that overexpression of SHANK2 in cytoplasm was inversely correlated with Yes1-associated transcriptional regulator (YAP) expression, suggesting that SHANK2 may play a role in suppressing the Hippo pathway in GC. In primary GC samples, both overexpression of SHANK2 in cytoplasm and low expression of SHANK2 in nucleus, which are defined as high SHANK2 index, correlated with more aggressive venous invasion, advanced tumor and nodal stage. Patients with high SHANK2 index tumors had a lower overall survival rate than those with non-expressing tumors. Multivariate analysis demonstrated that high SHANK2 index was independently associated with poor outcomes.
Conclusions: These findings suggest that SHANK2 plays a crucial role in tumor malignant potential through the Hippo pathway suppression and highlight its usefulness as a prognostic factor and potential therapeutic target in GC.
期刊介绍:
The American Journal of Cancer Research (AJCR) (ISSN 2156-6976), is an independent open access, online only journal to facilitate rapid dissemination of novel discoveries in basic science and treatment of cancer. It was founded by a group of scientists for cancer research and clinical academic oncologists from around the world, who are devoted to the promotion and advancement of our understanding of the cancer and its treatment. The scope of AJCR is intended to encompass that of multi-disciplinary researchers from any scientific discipline where the primary focus of the research is to increase and integrate knowledge about etiology and molecular mechanisms of carcinogenesis with the ultimate aim of advancing the cure and prevention of this increasingly devastating disease. To achieve these aims AJCR will publish review articles, original articles and new techniques in cancer research and therapy. It will also publish hypothesis, case reports and letter to the editor. Unlike most other open access online journals, AJCR will keep most of the traditional features of paper print that we are all familiar with, such as continuous volume, issue numbers, as well as continuous page numbers to retain our comfortable familiarity towards an academic journal.