Dual role of sprouty2 as an inhibitor of RAS/ERK-driven proliferation and a promoter of cancer invasion in KRAS wild-type colorectal cancer
Chung-Ta Lee
Department of Pathology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
Department of Pathology, National Cheng Kung University Hospital, Dou-Liou Branch, Douliu City, Yunlin County, Taiwan
Search for more papers by this authorChien-An Chu
Department of Pathology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
Search for more papers by this authorYu-Ming Wang
College of Medicine, Institute of Molecular Medicine, National Cheng Kung University, Tainan, Taiwan
Search for more papers by this authorYi-Wen Wang
Department of Pathology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
Search for more papers by this authorYi-Lin Chen
Department of Pathology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
Search for more papers by this authorChung-Liang Ho
Department of Pathology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
Search for more papers by this authorYu-Min Yeh
Department of Oncology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
Search for more papers by this authorPeng-Chan Lin
Department of Oncology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
Department of Genomic Medicine, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
College of Electrical Engineering and Computer Science, Institute of Medical Informatics, National Cheng Kung University, Tainan, Taiwan
Search for more papers by this authorBo-Wen Lin
Department of Surgery, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
Search for more papers by this authorPo-Chuan Chen
Department of Surgery, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
Search for more papers by this authorShang-Hung Chen
Department of Oncology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
Search for more papers by this authorRen-Hao Chan
Department of Surgery, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
Search for more papers by this authorChen Chang
Department of Pathology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
Search for more papers by this authorCorresponding Author
Nan-Haw Chow
Department of Pathology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
College of Medicine, Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan
Correspondence Nan-Haw Chow, Department of Pathology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, 138 Sheng-Li Rd, Tainan 704302, Taiwan.
Email: [email protected]
Search for more papers by this authorChung-Ta Lee
Department of Pathology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
Department of Pathology, National Cheng Kung University Hospital, Dou-Liou Branch, Douliu City, Yunlin County, Taiwan
Search for more papers by this authorChien-An Chu
Department of Pathology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
Search for more papers by this authorYu-Ming Wang
College of Medicine, Institute of Molecular Medicine, National Cheng Kung University, Tainan, Taiwan
Search for more papers by this authorYi-Wen Wang
Department of Pathology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
Search for more papers by this authorYi-Lin Chen
Department of Pathology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
Search for more papers by this authorChung-Liang Ho
Department of Pathology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
Search for more papers by this authorYu-Min Yeh
Department of Oncology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
Search for more papers by this authorPeng-Chan Lin
Department of Oncology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
Department of Genomic Medicine, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
College of Electrical Engineering and Computer Science, Institute of Medical Informatics, National Cheng Kung University, Tainan, Taiwan
Search for more papers by this authorBo-Wen Lin
Department of Surgery, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
Search for more papers by this authorPo-Chuan Chen
Department of Surgery, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
Search for more papers by this authorShang-Hung Chen
Department of Oncology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
Search for more papers by this authorRen-Hao Chan
Department of Surgery, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
Search for more papers by this authorChen Chang
Department of Pathology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
Search for more papers by this authorCorresponding Author
Nan-Haw Chow
Department of Pathology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
College of Medicine, Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan
Correspondence Nan-Haw Chow, Department of Pathology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, 138 Sheng-Li Rd, Tainan 704302, Taiwan.
Email: [email protected]
Search for more papers by this authorAbstract
Sprouty2 (SPRY2) is known to inhibit the RAS/MAPK/ERK pathway, and is a potential study target for cancer. The effect of SPRY2 in colorectal cancer (CRC) and whether it is influenced by KRAS mutation are not known. We manipulated SPRY2 gene expression and used an activating KRAS-mutant plasmid to determine its effect on CRC cell function in vitro and/or in vivo. We performed SPRY2 immunohistochemical staining in 143 CRC specimens and analyzed the staining results with various clinicopathological characteristics in relation to KRAS mutation status. SPRY2 knockdown in Caco-2 cells carrying the wild-type (WT) KRAS gene upregulated phosphorylated ERK (p-ERK) levels and increased cell proliferation in vitro, but inhibited cell invasion. However, SPRY2 knockdown in SW480 cells (activating KRAS mutant) or Caco-2 cells transfected with KRAS-mutant plasmid did not significantly alter p-ERK levels, cell proliferation, or invasion. The xenografts of SPRY2-knockdown Caco-2 cells were larger with less deep muscle invasion than those of control cells. The clinical cohort study revealed a positive association of SPRY2 protein expression with pT status, lymphovascular invasion, and perineural invasion in KRAS-WT CRCs. However, the associations were not observed in KRAS-mutant CRCs. Interestingly, high SPRY2 expression was related to shorter cancer-specific survival in both KRAS-WT and KRAS-mutant CRC patients. Our study demonstrated the dual role of SPRY2 as an inhibitor of RAS/ERK-driven proliferation and as a promoter of cancer invasion in KRAS-WT CRC. SPRY2 may promote the invasion and progression of KRAS-WT CRC, and might also enhance KRAS-mutant CRC progression through pathways other than invasion.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflict of interest.
Open Research
DATA AVAILABILITY STATEMENT
The data sets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Supporting Information
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