RHBDD1 promotes colorectal cancer metastasis through the Wnt signaling pathway and its downstream target ZEB1
Abstract Background 40–50% of colorectal cancer (CRC) patients develop metastatic disease; the presence of metastasis hinders the effective treatment of cancer through surgery, chemotherapy and radiotherapy, which makes 5-year survival rate extremely low; therefore, studying CRC metastasis is crucia...
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2018-02-01
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Series: | Journal of Experimental & Clinical Cancer Research |
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Online Access: | http://link.springer.com/article/10.1186/s13046-018-0687-5 |
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Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Mengmeng Zhang Fei Miao Rong Huang Wenjie Liu Yuechao Zhao Tao Jiao Yalan Lu Fan Wu Xiaojuan Wang Han Wang Hong Zhao Hongge Ju Shiying Miao Linfang Wang Wei Song |
spellingShingle |
Mengmeng Zhang Fei Miao Rong Huang Wenjie Liu Yuechao Zhao Tao Jiao Yalan Lu Fan Wu Xiaojuan Wang Han Wang Hong Zhao Hongge Ju Shiying Miao Linfang Wang Wei Song RHBDD1 promotes colorectal cancer metastasis through the Wnt signaling pathway and its downstream target ZEB1 Journal of Experimental & Clinical Cancer Research RHBDD1 Colorectal cancer Metastasis Wnt signaling pathway ZEB1 |
author_facet |
Mengmeng Zhang Fei Miao Rong Huang Wenjie Liu Yuechao Zhao Tao Jiao Yalan Lu Fan Wu Xiaojuan Wang Han Wang Hong Zhao Hongge Ju Shiying Miao Linfang Wang Wei Song |
author_sort |
Mengmeng Zhang |
title |
RHBDD1 promotes colorectal cancer metastasis through the Wnt signaling pathway and its downstream target ZEB1 |
title_short |
RHBDD1 promotes colorectal cancer metastasis through the Wnt signaling pathway and its downstream target ZEB1 |
title_full |
RHBDD1 promotes colorectal cancer metastasis through the Wnt signaling pathway and its downstream target ZEB1 |
title_fullStr |
RHBDD1 promotes colorectal cancer metastasis through the Wnt signaling pathway and its downstream target ZEB1 |
title_full_unstemmed |
RHBDD1 promotes colorectal cancer metastasis through the Wnt signaling pathway and its downstream target ZEB1 |
title_sort |
rhbdd1 promotes colorectal cancer metastasis through the wnt signaling pathway and its downstream target zeb1 |
publisher |
BMC |
series |
Journal of Experimental & Clinical Cancer Research |
issn |
1756-9966 |
publishDate |
2018-02-01 |
description |
Abstract Background 40–50% of colorectal cancer (CRC) patients develop metastatic disease; the presence of metastasis hinders the effective treatment of cancer through surgery, chemotherapy and radiotherapy, which makes 5-year survival rate extremely low; therefore, studying CRC metastasis is crucial for disease therapy. In the present study, we investigated the role of rhomboid domain containing 1 (RHBDD1) in tumor metastasis of CRC. Methods The expression of RHBDD1 was analyzed in 539 colorectal tumor tissues for its correlation with lymphatic metastasis and distal metastasis. Transwell assay in vitro and pleural metastasis analysis in vivo were performed to determine the functions of RHBDD1 during CRC cells metastasis. RNA-seq analysis, TOP/FOP flash reporter assay, western blot and transwell assay were performed to investigate the underlying mechanism for the function of RHBDD1 on Wnt signaling pathway. Bioinformatics analysis was conducted to investigate epithelial-mesenchymal transition (EMT) and stemness in HCT-116 cells. Tissue microarray analysis, Q-PCR and western blot were performed to determine the correlation of RHBDD1 and Zinc Finger E-Box Binding Homeobox 1 (ZEB1). Results In this study, we found that RHBDD1 expression was positively correlated with lymphatic metastasis and distal metastasis in 539 colorectal tumor tissues. RHBDD1 expression can promote CRC cells metastasis in vitro and in vivo. RNA-Seq analysis showed that the Wnt signaling pathway played a key role in this metastatic regulation. RHBDD1 mainly regulated ser552 and ser675 phosphorylation of β-catenin to activate the Wnt signaling pathway. Rescuing ser552 and ser675 phosphorylation of β-catenin resulted in the recovery of signaling pathway activity, migration, and invasion in CRC cells. RHBDD1 promoted EMT and a stem-like phenotype of CRC cells. RHBDD1 regulated the Wnt/β-catenin target gene ZEB1, a potent EMT activator, at the RNA and protein levels. Clinically, RHBDD1 expression was positively correlated with ZEB1 at the protein level in 71 colon tumor tissues. Conclusions Our findings therefore indicated that RHBDD1 can promote CRC metastasis through the Wnt signaling pathway and ZEB1. RHBDD1 may become a new therapeutic target or clinical biomarker for metastatic CRC. |
topic |
RHBDD1 Colorectal cancer Metastasis Wnt signaling pathway ZEB1 |
url |
http://link.springer.com/article/10.1186/s13046-018-0687-5 |
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doaj-adbdbadc0231456e86133afae0fd93b32020-11-25T00:46:09ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662018-02-0137111410.1186/s13046-018-0687-5RHBDD1 promotes colorectal cancer metastasis through the Wnt signaling pathway and its downstream target ZEB1Mengmeng Zhang0Fei Miao1Rong Huang2Wenjie Liu3Yuechao Zhao4Tao Jiao5Yalan Lu6Fan Wu7Xiaojuan Wang8Han Wang9Hong Zhao10Hongge Ju11Shiying Miao12Linfang Wang13Wei Song14State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical CollegeState Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical CollegeState Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical CollegeState Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical CollegeState Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical CollegeState Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical CollegeState Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical CollegeState Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical CollegeState Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical CollegeState Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical CollegeDepartment of Abdominal Surgical Oncology, Cancer Hospital & Institute, Chinese Academy of Medical SciencesDepartment of Pathology, Baotou Medical CollegeState Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical CollegeState Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical CollegeState Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical CollegeAbstract Background 40–50% of colorectal cancer (CRC) patients develop metastatic disease; the presence of metastasis hinders the effective treatment of cancer through surgery, chemotherapy and radiotherapy, which makes 5-year survival rate extremely low; therefore, studying CRC metastasis is crucial for disease therapy. In the present study, we investigated the role of rhomboid domain containing 1 (RHBDD1) in tumor metastasis of CRC. Methods The expression of RHBDD1 was analyzed in 539 colorectal tumor tissues for its correlation with lymphatic metastasis and distal metastasis. Transwell assay in vitro and pleural metastasis analysis in vivo were performed to determine the functions of RHBDD1 during CRC cells metastasis. RNA-seq analysis, TOP/FOP flash reporter assay, western blot and transwell assay were performed to investigate the underlying mechanism for the function of RHBDD1 on Wnt signaling pathway. Bioinformatics analysis was conducted to investigate epithelial-mesenchymal transition (EMT) and stemness in HCT-116 cells. Tissue microarray analysis, Q-PCR and western blot were performed to determine the correlation of RHBDD1 and Zinc Finger E-Box Binding Homeobox 1 (ZEB1). Results In this study, we found that RHBDD1 expression was positively correlated with lymphatic metastasis and distal metastasis in 539 colorectal tumor tissues. RHBDD1 expression can promote CRC cells metastasis in vitro and in vivo. RNA-Seq analysis showed that the Wnt signaling pathway played a key role in this metastatic regulation. RHBDD1 mainly regulated ser552 and ser675 phosphorylation of β-catenin to activate the Wnt signaling pathway. Rescuing ser552 and ser675 phosphorylation of β-catenin resulted in the recovery of signaling pathway activity, migration, and invasion in CRC cells. RHBDD1 promoted EMT and a stem-like phenotype of CRC cells. RHBDD1 regulated the Wnt/β-catenin target gene ZEB1, a potent EMT activator, at the RNA and protein levels. Clinically, RHBDD1 expression was positively correlated with ZEB1 at the protein level in 71 colon tumor tissues. Conclusions Our findings therefore indicated that RHBDD1 can promote CRC metastasis through the Wnt signaling pathway and ZEB1. RHBDD1 may become a new therapeutic target or clinical biomarker for metastatic CRC.http://link.springer.com/article/10.1186/s13046-018-0687-5RHBDD1Colorectal cancerMetastasisWnt signaling pathwayZEB1 |