Loss of large tumor suppressor 1 promotes growth and metastasis of gastric cancer cells through upregulation of the YAP signaling
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Jing Zhang1,*, Ge Wang1,*, Shao-Jun Chu2, Jin-Shui Zhu1, Rui Zhang1, Wen-Wen Lu1, Li-Qiong Xia1, Yun-Min Lu1, Wei Da1, Qun Sun1
1Department of Gastroenterology, Shanghai Jiao Tong University Affiliated Shanghai Sixth People's Hospital, Shanghai 200233, China
2Department of Gerontology, Shanghai Jiao Tong University Affiliated Shanghai Sixth People's Hospital, Shanghai 200233, China
*These authors have contributed equally to this work
Jin-Shui Zhu, e-mail: firstname.lastname@example.org
Keywords: large tumor suppressor 1, YAP, metastasis, prognosis, gastric cancer
Received: June 28, 2015 Accepted: January 05, 2016 Published: February 22, 2016
Accumulating evidence shows that large tumor suppressor 1 (LATS1) as a novel resident governor of cellular homeostasis is implicated in multiple tumorigenic properties including cell growth, apoptosis and metastasis. However, the contribution of LATS1 to gastric carcinoma (GC) remains unclear. The correlation of LATS1 expression with clinicopathologic characteristics, GC prognosis and recurrence was analyzed by immunohistochemistry, Univariate and Kaplan-Meier analysis. Functional experiments were performed to investigate biological behaviors of GC cells and underlying molecular mechanisms. Tumor growth and metastasis was assessed in vivo using orthotopic implantation GC models in severe combined immune deficiency (SCID) mice. Consequently, decreased LATS1 expression was significantly associated with the lymph node metastasis, poor prognosis and recurrence. Ectopic expression of LATS1 decreased GC cell proliferation and invasion in vitro and inhibited tumor growth and liver metastasis in vivo, but depletion of LATS1 expression restored the invasive phenotype. Further observation indicated that YAP pathway was required for LATS1-induced inhibition of cell growth and invasion, and LATS1 restrained nuclear transfer of YAP, downregulated YAP, PCNA, CTGF, MMP-2, MMP-9, Bcl-2 and CyclinD1 expression and upregulated p-YAP and Bax expression. Our findings suggest that LATS1 is a potential candidate tumor suppressor and inhibits the growth and metastasis of GC cells via downregulation of the YAP signaling.
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