FOXC2 promotes colorectal cancer metastasis by directly targeting MET.
Metastasis is the major cause of death in colorectal cancer (CRC). Although multiple genes have been identified to be responsible for the development of CRC, the molecular changes that enable CRC cells to undergo early local invasion and to form distant metastatic colonies still remain largely unknown. Herein, we investigated the role of Forkhead box protein C2 (FOXC2) and explored the underlying mechanisms in invasion and metastasis of CRC. We show that both high FOXC2 expression and nuclear localization of FOXC2 are significantly correlated with advanced TNM (T=primary tumor; N=regional lymph nodes; M=distant metastasis) stages. FOXC2 enhanced the invasive abilities of CRC cells in vitro and promoted local invasion and distant metastasis in an orthotopic mouse metastatic model of CRC. Microarray analysis revealed that overexpression of FOXC2 increased the proto-oncogene MET tyrosine kinase expression and activated the hepatocyte growth factor (HGF)-MET signaling pathway. Furthermore, luciferase reporter assays and chromatin immunoprecipitation assays revealed that FOXC2 directly associated with MET promoter to increase the transcriptional activity of MET. Inhibition of MET attenuates the invasive phenotype and metastatic potential of FOXC2-overexpressing CRC cells, indicating that MET is a major mediator of FOXC2-promoted metastasis. In addition, FOXC2 expression was positively correlated with MET expression in CRC tissue samples. Our findings suggest that FOXC2 has a crucial role in CRC metastasis by regulating HGF-MET signaling via inducing MET expression, highlighting FOXC2 as a potential therapeutic target for preventing or reducing metastasis in CRC.
1] Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China [2] Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China [3] Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, China.
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Cui
1] Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China [2] Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China [3] Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, China.
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HL
Jiao
1] Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China [2] Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China [3] Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, China.
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YP
Ye
1] Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China [2] Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China [3] Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, China.
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Chen
1] Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China [2] Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China [3] Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, China.
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JX
Wang
1] Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China [2] Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China [3] Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, China.
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Tang
1] Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China [2] Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China [3] Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, China.
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TT
Li
1] Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China [2] Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China [3] Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, China.
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J
Lin
1] Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China [2] Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China [3] Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, China.
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Qi
1] Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China [2] Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China [3] Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, China.
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Wu
1] Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China [2] Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China [3] Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, China.
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Wang
Guangdong Provincial Key Laboratory of Gastroenterology and Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
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MR
He
1] Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China [2] Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China [3] Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, China.
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L
Liang
Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
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XW
Bian
1] Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China [2] Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China [3] Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, China.
W-T
WT
Liao
1] Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China [2] Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China [3] Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, China.
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YQ
Ding
D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology*; D051858:Forkhead Transcription Factors / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D017228:Hepatocyte Growth Factor / Q000235:genetics; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000473:pathology; D000090063:Proto-Oncogene Mas; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics
D051858:Forkhead Transcription Factors; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; C082078:mesenchyme fork head 1 protein; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met