Frequent Loss of NISCH Promotes Tumor Proliferation and Invasion in Ovarian Cancer via Inhibiting the FAK Signal Pathway

Abstract

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.

Breast Cancer Tumor Suppressors: A Special Emphasis on Novel Protein Nischarin

“…This decreased expression of Nischarin is associated with invasiveness, tumor stage, lymph node metastasis, and histologic tumor grade (35). Interestingly, ovarian cancer patients with Nischarin expression have a better overall survival than nonexpressing patients (35). The NISH promoter is hypermethylated in 36.7% of ovarian cancers (35).…”

“…Nischarin is a tumor suppressor of ovarian cancer Nischarin expression is downregulated in ovarian cancer tissues (35). This decreased expression of Nischarin is associated with invasiveness, tumor stage, lymph node metastasis, and histologic tumor grade (35).…”

“…Interestingly, ovarian cancer patients with Nischarin expression have a better overall survival than nonexpressing patients (35). The NISH promoter is hypermethylated in 36.7% of ovarian cancers (35). Overexpression of this tumor suppressor in an ovarian cancer cell line imposes a G 1 phase arrest and cyclin D1 downregulation, which leads to decelerated cell proliferation (35).…”

“…The NISH promoter is hypermethylated in 36.7% of ovarian cancers (35). Overexpression of this tumor suppressor in an ovarian cancer cell line imposes a G 1 phase arrest and cyclin D1 downregulation, which leads to decelerated cell proliferation (35). It has been shown that Nischarin exerts its tumor-suppressive effects through FAK in ovarian cancer (35).…”

“…Overexpression of this tumor suppressor in an ovarian cancer cell line imposes a G 1 phase arrest and cyclin D1 downregulation, which leads to decelerated cell proliferation (35). It has been shown that Nischarin exerts its tumor-suppressive effects through FAK in ovarian cancer (35). The role of Nischarin in ovarian cancer has recently been discovered and further studies are needed to understand the tumor-suppressive effect of Nischarin in ovarian cancer.…”