Frequent Loss of NISCH Promotes Tumor Proliferation and Invasion in Ovarian Cancer via Inhibiting the FAK Signal Pathway.
NISCH encodes the imidazoline receptor Nischarin and is a known tumor suppressor in many human malignancies; however, its roles in ovarian cancer are still largely unknown. Here, we aim to investigate the biologic functions of NISCH in ovarian cancer. We found that NISCH was significantly downregulated, which correlated considerably with advanced tumor stage, poor differentiation, lymph node metastasis, and the serous/mucinous subtypes in a panel of ovarian cancer tissues. Moreover, NISCH gene silencing was mainly the product of promoter hypermethylation, which could be reversed by treatment with 5-aza-dC. In vitro, NISCH overexpression suppressed cell proliferation and colony formation by hindering cell-cycle progression, whereas the opposite was observed in NISCH knockdown counterparts. In vivo, abundant NISCH expression hindered the growth of HO8910 xenografts, whereas NISCH knockdown accelerated the growth of SKOV3 xenografts. In addition, NISCH significantly attenuated cell invasion by inhibiting the phosphorylation of FAK and ERK, which could be neutralized by PF-562271 (a FAK/Pyk2 inhibitor). Accordingly, NISCH knockdown xenografts exhibited increased peritoneal/pelvic metastases that were not present in counterparts treated with PF-562271. Furthermore, NISCH expression in primary ovarian cancer cells predicted a cellular resistance to PF-562271. In conclusion, we showed that NISCH was frequently silenced by promoter hypermethylation in human ovarian cancer. NISCH manipulated cellular proliferation and invasion by arresting cell cycle and inhibiting the FAK signal. Our findings revealed the biologic functions of NISCH in ovarian cancer, and might be useful for treating patients with aberrant expression of NISCH.
Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. Key-Discipline Laboratory of Clinical Medicine Henan, Zhengzhou, China.
Jing
J
Li
Department of Obstetrics and Gynecology, International Peace Maternity and Child Health Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.
Xiaoying
X
He
Department of Obstetrics and Gynecology, the Affiliated Hospital of Jiangnan University and The 4th People's Hospital of Wuxi, Jiangsu Province, China.
Ruofan
R
Dong
Department of Obstetrics and Gynecology, the Affiliated Hospital of Jiangnan University and The 4th People's Hospital of Wuxi, Jiangsu Province, China.
Yuan
Y
Wang
Department of Obstetrics and Gynecology, the Affiliated Hospital of Jiangnan University and The 4th People's Hospital of Wuxi, Jiangsu Province, China.
Jinjin
J
Yu
Key-Discipline Laboratory of Clinical Medicine Henan, Zhengzhou, China. Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. haifengqiu120@gmail.com.
Haifeng
H
Qiu
D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D015536:Down-Regulation; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D006801:Humans; D054755:Imidazoline Receptors / Q000235:genetics* / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism*; D019656:Loss of Heterozygosity; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D015398:Signal Transduction
D054755:Imidazoline Receptors; D047908:Intracellular Signaling Peptides and Proteins; C458505:NISCH protein, human; D000077209:Decitabine; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D001374:Azacitidine