Dataset Information

FAM83H and SCRIB stabilize ?-catenin and stimulate progression of gastric carcinoma.

ABSTRACT: FAM83H primarily is known for its function in tooth development. Recently, a role for FAM83H in tumorigenesis, conjunction with MYC and ?-catenin, has been suggested. Analysis of public data indicates that FAM83H expression is closely associated with SCRIB expression in human gastric cancers. Therefore, this study investigated the roles of FAM83H and SCRIB in 200 human gastric cancers and gastric cancer cells. In human gastric carcinomas, both the individual and combined expression patterns of the nuclear FAM83H and SCRIB were independent indicators of shorter survival of gastric carcinoma patients. In MKN-45 and NCI-N87 gastric cancer cells, the expression of FAM83H and SCRIB were associated with proliferation and invasiveness of cells. FAM83H-mediated in vivo tumor growth was attenuated with knock-down of SCRIB. Moreover, immunoprecipitation indicates that FAM83H, SCRIB, and ?-catenin, form a complex, and knock-down of either FAM83H or SCRIB accelerated proteasomal degradation of ?-catenin. In conclusion, this study has found that the individual and combined expression patterns of nuclear FAM83H and SCRIB are prognostic indicators of gastric carcinomas and further suggests that FAM83H and SCRIB are involved in the progression of gastric carcinomas by stabilizing ?-catenin.

SUBMITTER: Hussein UK

PROVIDER: S-EPMC7343515 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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FAM83H and SCRIB stabilize β-catenin and stimulate progression of gastric carcinoma.

Hussein Usama Khamis UK Ha Sang Hoon SH Ahmed Asmaa Gamal AG Kim Kyoung Min KM Park See-Hyoung SH Kim Chan Young CY Kwon Keun Sang KS Zhang Zhongkai Z Lee Sang-A SA Park Ho Sung HS Park Byung-Hyun BH Lee Ho H Chung Myoung Ja MJ Moon Woo Sung WS Kang Myoung Jae MJ Jang Kyu Yun KY

Aging 20200620 12

FAM83H primarily is known for its function in tooth development. Recently, a role for FAM83H in tumorigenesis, conjunction with MYC and β-catenin, has been suggested. Analysis of public data indicates that FAM83H expression is closely associated with SCRIB expression in human gastric cancers. Therefore, this study investigated the roles of FAM83H and SCRIB in 200 human gastric cancers and gastric cancer cells. In human gastric carcinomas, both the individual and combined expression patterns of t ...[more]

PMID: 32564009

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Project description:BACKGROUND:FAM83H was initially identified as a protein essential for dental enamel formation. Recent reports have shown that FAM83H is also involved in the progression of human cancers in conjunction with tumor-associated molecules, such as MYC and ?-catenin. However, the role of FAM83H in sarcoma has not yet been investigated. METHODS:The expression and roles of FAM83H and ?-catenin were evaluated in human osteosarcomas from 34 patients and osteosarcoma cells. RESULTS:The expression of nuclear FAM83H, cytoplasmic FAM83H, and ?-catenin were significantly associated with each other and significantly associated with shorter survival of osteosarcoma patients by univariate analysis. In multivariate analysis, cytoplasmic expression of FAM83H was an independent indicator of shorter survival of osteosarcoma patients (overall survival; P?<? 0.001, relapse-free survival; P?<? 0.001). In U2OS, MG63, and KHOS/NP osteosarcoma cells, the knock-down of FAM83H decreased proliferation and invasion activity and overexpression of FAM83H increased proliferation and invasion activity. In KHOS/NP cells, knock-down of FAM83H significantly inhibited, and overexpression of FAM83H significantly increased in vivo growth of cells. In addition, the knock-down of FAM83H decreased protein expression of ?-catenin, active ?-catenin, cyclin D1, vimentin, and snail. Overexpression of FAM83H increased protein expression of ?-catenin, active ?-catenin, cyclin D1, vimentin, and snail. However, the expression of ?-catenin mRNA was not significantly altered with knock-down or overexpression of FAM83H. In addition, FAM83H and ?-catenin shown to directly interact via immunoprecipitation and nuclear and cytoplasmic localization of ?-catenin was decreased with knock-down of FAM83H. Moreover, the ubiquitination and proteasomal degradation of ?-catenin was increased with knock-down of FAM83H. CONCLUSIONS:This study suggests that FAM83H is involved in the progression of osteosarcomas via a mechanism involving the stabilization of ?-catenin and the promotion of proliferation and invasiveness of osteosarcomas.

Project description:Cancer stem cells (CSCs) are the key factor in determining cancer recurrence, metastasis, chemoresistance and patient prognosis in hepatocellular carcinoma (HCC). The role of miR-5188 in cancer stemness has never been documented. In this study, we investigated the clinical and biological roles of miR-5188 in HCC. Methods: MiRNA expression in HCC was analyzed by bioinformatics analysis and in situ hybridization. The biological effect of miR-5188 was demonstrated in both in vitro and in vivo studies through the ectopic expression of miR-5188. The target gene and molecular pathway of miR-5188 were characterized using bioinformatics tools, dual-luciferase reporter assays, gene knockdown, and rescue experiments. Results: MiR-5188 was shown to be upregulated and confer poor prognosis in HCC patient data from TCGA database. MiR-5188 was subsequently identified as a significant inducer of cancer stemness that promotes HCC pathogenesis. Specifically, the targeting of miR-5188 by its antagomir markedly prolonged the survival time of HCC-bearing mice and improved HCC cell chemosensitivity in vivo. Mechanistic analysis indicated that miR-5188 directly targets FOXO1, which interacts with ?-catenin in the cytoplasm to reduce the nuclear translocation of ?-catenin and promotes the activation of Wnt signaling and downstream tumor stemness, EMT, and c-Jun. Moreover, c-Jun transcriptionally activates miR-5188 expression, forming a positive feedback loop. Interestingly, the miR-5188-FOXO1/?-catenin-c-Jun feedback loop was induced by hepatitis X protein (HBX) through Wnt signaling and participated in the HBX-induced pathogenesis of HCC. Finally, analyses of transcriptomics data and our clinical data supported the significance of the abnormal expression of the miR-5188 pathway in HCC pathogenesis. Conclusions: These findings present the inhibition of miR-5188 as a novel strategy for the efficient elimination of CSCs to prevent tumor metastasis, recurrence and chemoresistance in patients with hepatocellular carcinoma. Our study highlights the importance of miR-5188 as a tumor stemness inducer that acts as a potential target for HCC treatment.

Dataset Information

FAM83H and SCRIB stabilize ?-catenin and stimulate progression of gastric carcinoma.

Publications

FAM83H and SCRIB stabilize β-catenin and stimulate progression of gastric carcinoma.

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