Silencing of WISP3 suppresses gastric cancer cell proliferation and metastasis and inhibits Wnt/β-catenin signaling.
CCN6/Wnt1-inducible signaling protein-3 (CCN6/WISP3) is a cysteine-rich protein that belongs to the CCN (Cyr61, CTGF, Nov) family of matricellular proteins, which are often dysregulated in cancers. However, the functional role and clinical significance of WISP3 in gastric cancer remain unclear. In this study, we found that silencing of WISP3 suppressed gastric cancer cell proliferation, migration and invasion. Cell adhesion to collagens (collagen I and IV), but not to fibronectin, were significantly inhibited by silencing of WISP3. Furthermore, silencing of WISP3 prevented β-catenin transferring from cell cytoplasm to nuclear, and suppressed canonical Wnt/β-catenin signaling and its downstream target genes, cyclin D1 and TCF-4. By immunohistochemical analysis of 379 patients, we found that the expression of WISP3 is closely associated with gastric cancer size and tumor invasion, and indicates a poor prognosis in both test cohort (253 patients) and validation cohort (126 patients). Moreover, the expression of WISP3 was positively correlated with the expression of cyclin D1 and TCF-4 in gastric cancer tissues. Taken together, our data suggests that WISP3 might be a promising prognostic factor and WISP3-Wnt/β-catenin axis may be a new therapeutic target for the intervention of gastric cancer growth and metastasis.
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine Shanghai 200240, P.R. China.
Fang
F
Fang
Department of General Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine Shanghai, China.
Wen-Yi
WY
Zhao
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine Shanghai 200240, P.R. China.
Rong-Kun
RK
Li
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine Shanghai 200240, P.R. China.
Xiao-Mei
XM
Yang
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine Shanghai 200240, P.R. China.
Jun
J
Li
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine Shanghai 200240, P.R. China.
Jun-Ping
JP
Ao
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine Shanghai 200240, P.R. China.
Shu-Heng
SH
Jiang
Department of General Surgery, Central Hospital of Fengxian District 6600 Nan Feng Road, Shanghai 201400, China.
Fan-Zhi
FZ
Kong
Department of General Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine Shanghai, China.
Lin
L
Tu
Department of General Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine Shanghai, China.
Chun
C
Zhuang
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine Shanghai 200240, P.R. China.
Wen-Xin
WX
Qin
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine Shanghai 200240, P.R. China.
Ping
P
He
Department of Endoscopy, Cancer Hospital, and Department of Oncology, Shanghai Medical College, Fudan University Shanghai 200032, China.
Wen-Ming
WM
Zhang
Department of General Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine Shanghai, China.
Hui
H
Cao
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine Shanghai 200240, P.R. China.
Zhi-Gang
ZG
Zhang
D021581:Active Transport, Cell Nucleus; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D055511:CCN Intercellular Signaling Proteins / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism; D015536:Down-Regulation; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D011379:Prognosis; D034622:RNA Interference; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D047368:Tumor Burden; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism*
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D055511:CCN Intercellular Signaling Proteins; C400081:CCN6 protein, human; C530104:CCND1 protein, human; C495270:CTNNB1 protein, human; D016326:Extracellular Matrix Proteins; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D051176:beta Catenin; D019938:Cyclin D1
WISP3; canonical Wnt signaling; gastric cancer cell; invasion; proliferation