REG4 is an indicator for KRAS mutant lung adenocarcinoma with TTF-1 low expression
Autor: | Shenglin Huang, Si Sun, Lanlin Zhang, Hui Yu, Qifeng Wang, Xianghua Wu, Xun Ye, Jialei Wang, Xingjiang Hu, Zhihuang Hu, Jianhua Chang |
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Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
Male Cancer Research Lung Neoplasms Down-Regulation Mice Nude Adenocarcinoma of Lung Pancreatitis-Associated Proteins Biology medicine.disease_cause Cohort Studies Proto-Oncogene Proteins p21(ras) 03 medical and health sciences Mice 0302 clinical medicine CDKN2A Cell Line Tumor medicine Biomarkers Tumor Gene silencing Animals Humans Lung cancer Gene knockdown Mice Inbred BALB C Cancer General Medicine medicine.disease DNA-Binding Proteins Gene Expression Regulation Neoplastic 030104 developmental biology Cell Transformation Neoplastic Oncology 030220 oncology & carcinogenesis Cancer research Adenocarcinoma Female Mutant Proteins KRAS Carcinogenesis Transcription Factors |
Zdroj: | Journal of cancer research and clinical oncology. 145(9) |
ISSN: | 1432-1335 |
Popis: | Recent research has classified lung adenocarcinoma patients with KRAS mutation into three subtypes by co-occurring genetic events in TP53 (KP subgroup), STK11/LKB1 (KL subgroup) and CDKN2A/B inactivation plus TTF-1 low expression (KC subgroup). The aim of this study was to identify valuable biomarkers by searching the candidate molecules that contribute to lung adenocarcinoma pathogenesis, especially KC subtype. We analyzed the publicly available database and identified the candidate REG4 using the E-GEOD-31210 dataset, and then confirmed by TCGA dataset. In addition, an independent cohort of 55 clinical samples was analyzed by quantitative real-time PCR analysis. Functional studies and RNA sequencing were performed after silencing the REG4 expression. REG4, an important regulator of gastro-intestinal carcinogenesis, was highly expressed in KRAS mutant lung adenocarcinoma with low expression of TTF-1 (KC subtype). The results were validated both by gene expression analysis and immunohistochemistry study in an independent 55 clinical samples from Fudan University Shanghai Cancer Center. Further in vitro and in vivo functional assays revealed silencing REG4 expression significantly reduces cancer cell proliferation and tumorigenesis. Moreover, RNA sequencing and GSEA analysis displayed that REG4 knockdown might induce cell cycle arrest by regulating G2/M checkpoint and E2F targets. Our results indicate that REG4 plays an important role in KRAS-driven lung cancer pathogenesis and is a novel biomarker of lung adenocarcinoma subtype. Future studies are required to clarify the underlying mechanisms of REG4 in the division and proliferation of KC tumors and its potential therapeutic value. |
Databáze: | OpenAIRE |
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