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Frequent Loss of NISCH Promotes Tumor Proliferation and Invasion In Published OnlineFirst February 27, 2015; DOI: 10.1158/1535-7163.MCT-14-0911 Cancer Biology and Signal Transduction Molecular Cancer Therapeutics Frequent Loss of NISCH Promotes Tumor Proliferation and Invasion in Ovarian Cancer via Inhibiting the FAK Signal Pathway Jing Li1,2, Xiaoying He3, Ruofan Dong4, Yuan Wang4, Jinjin Yu4, and Haifeng Qiu2,5 Abstract NISCH encodes the imidazoline receptor Nischarin and is a accelerated the growth of SKOV3 xenografts. In addition, NISCH known tumor suppressor in many human malignancies; how- significantly attenuated cell invasion by inhibiting the phos- ever, its roles in ovarian cancer are still largely unknown. Here, phorylation of FAK and ERK, which could be neutralized by PF- we aim to investigate the biologic functions of NISCH in ovarian 562271 (a FAK/Pyk2 inhibitor). Accordingly, NISCH knock- cancer. We found that NISCH was significantly downregulated, down xenografts exhibited increased peritoneal/pelvic metasta- which correlated considerably with advanced tumor stage, poor ses that were not present in counterparts treated with PF- differentiation, lymph node metastasis, and the serous/mucin- 562271. Furthermore, NISCH expression in primary ovarian ous subtypes in a panel of ovarian cancer tissues. Moreover, cancer cells predicted a cellular resistance to PF-562271. In NISCH gene silencing was mainly the product of promoter conclusion, we showed that NISCH was frequently silenced by hypermethylation, which could be reversed by treatment with promoter hypermethylation in human ovarian cancer. NISCH 5-aza-dC. In vitro, NISCH overexpression suppressed cell pro- manipulated cellular proliferation and invasion by arresting cell liferation and colony formation by hindering cell-cycle progres- cycle and inhibiting the FAK signal. Our findings revealed the sion, whereas the opposite was observed in NISCH knockdown biologic functions of NISCH in ovarian cancer, and might be counterparts. In vivo, abundant NISCH expression hindered the useful for treating patients with aberrant expression of NISCH. growth of HO8910 xenografts, whereas NISCH knockdown Mol Cancer Ther; 14(5); 1–11. Ó2015 AACR. Introduction III and IV, respectively (5–7). Similar to other malignancies, ovarian cancer is characterized by rapid proliferation, invasion, Ovarian cancer is the fifth leading cause of cancer-related deaths and the formation of regional/distant metastasis (8). Thus, a among the global female population, resulting in the highest deeper understanding of the mechanisms underlying the initia- mortality among all the gynecologic malignancies (1). In 2014, tion and progression of ovarian cancer is urgently needed. there were estimated 21,980 new cases of and 14,270 deaths The NISCH gene localizes on human chromosome 3p21.1 and caused by ovarian cancer in the United States (2). Unfortunately, encodes the imidazoline receptor Nischarin, which binds the more than 70% of the ovarian cancer patients present with cytoplasmic tail of a5 integrin to regulate its translocation from advanced stage disease (stage III/IV) at the initial diagnosis, and the cell membrane to endosomes (9). Recently, several lines of are thus given a poor prognosis (3, 4). Despite many advances in evidence indicate that Nischarin directly interacts with PAK1 surgical techniques and chemotherapy during the past decades, (p21-activated kinase1), LIMK (LIM domain kinase), Rac1 the 5-year survival rates remain as low as 35% and 20% for stages (Ras-related C3 botulinum toxin substrate 1), and LKB1 (liver kinase B1), to inhibit cellular migration and invasion (10–13). NISCH 1Department of Oncology, the First Affiliated Hospital of Zhengzhou is frequently silenced by loss of heterozygosity (LOH) University, Zhengzhou, China. 2Key-Discipline Laboratory of Clinical in human breast cancer, whereas its overexpression is sufficient to 3 Medicine Henan, Zhengzhou, China. Department of Obstetrics and attenuate tumor growth and metastasis via a5 integrin signaling Gynecology, International Peace Maternity and Child Health Hospital NISCH Affiliated to Shanghai Jiaotong University School of Medicine, Shang- pathway inhibition (14). The roles of in ovarian cancer are hai, China. 4Department of Obstetrics and Gynecology, the Affiliated largely unknown; therefore, we investigated the role of NISCH in Hospital of Jiangnan University and The 4th People's Hospital of Wuxi, ovarian cancer initiation and progression. Jiangsu Province, China. 5Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. Materials and Methods Note: Supplementary data for this article are available at Molecular Cancer Ovarian cancer tissue collection Therapeutics Online (http://mct.aacrjournals.org/). Two ovarian cancer tissue microarrays (OV952 and OV961) Corresponding Author: Haifeng Qiu, Department of Obstetrics and Gynecol- containing 12 normal ovaries, 38 serous, 28 endometrioid, 20 ogy, The First Affiliated Hospital of Zhengzhou University, No. 1, East Jianshe mucinous, and three clear cell ovarian cancers were purchased Road, Erqi district, Zhengzhou 450052, China. Phone: 0371-5675-5995; from Alenabio Biotechnology Company (Xi'an, Shanxi Province, Fax: 0371-5675-5995; E-mail: [email protected] China) for use in immunostaining assays. Another 30 ovarian doi: 10.1158/1535-7163.MCT-14-0911 cancer samples and adjacent normal ovary tissue collected at Ó2015 American Association for Cancer Research. the Affiliated Hospital of Jiangnan University (Wuxi, Jiangsu www.aacrjournals.org OF1 Downloaded from mct.aacrjournals.org on September 26, 2021. © 2015 American Association for Cancer Research. Published OnlineFirst February 27, 2015; DOI: 10.1158/1535-7163.MCT-14-0911 Li et al. ÀDDC Province, China) were used for real-time PCR, quantitative meth- expression of NISCH was calculated using the 2 t method ylation-specific PCR (QMSP), and LOH analysis. All patients were with b-actin as an internal control. staged and graded following the criteria of International Feder- ation of Gynecology and Obstetrics (FIGO) for ovarian cancer. DNA bisulfite modification and QMSP Patient follow-ups were performed every 6 months for all avail- Genomic DNA was extracted from 30 pair-matched ovarian able cases until July 30, 2014. This study was approved by the cancer tissues using a DNA Kit (Tiangen Biotech) and treated with ethical committee of the Affiliated Hospital of Jiangnan Univer- bisulfite using the EZ DNA Methylation-Gold Kit (Zymo sity and written consents were obtained from all participants. Research) according to the manufacturer's instructions. The mod- For primary cultures, 12 freshly obtained ovarian cancer tissues ified genomic DNA then served as template DNA for QMSP were minced with scalpels before digestion in 0.1% collagenase IA reactions with the primers and conditions described in Table 1. dissolved in DMEM (Gibco) containing 10% FBS (Gibco) for 2 Samples were defined to be hypermethylated if the relative level of hours at 37 C. After a short centrifugation, cancer cells were methylated DNA in which exceeded a set threshold determined by 5 suspended with DMEM to a density of approximately 1 Â 10 analyzing the overall methylation levels in the 30 pair-matched 4 cells/mL. For MTT assay, 1 Â 10 cells per well were plated into the tissues and considering the best sensitivity and specificity). 96-well plates and incubated overnight before the 72-hour treat- ment with PF-562271. 5-aza-dC treatment Cells (1 Â 106 cells/well) were seeded into 6-well plates and Immunohistochemical staining cultured overnight before treatment with 5 mmol/L 5-aza-dC All procedures were performed according to previously pub- (A3656; Sigma-Aldrich) or PBS vehicle for 48 hours. Real-time lished protocols (14). Anti-Nischarin mouse monoclonal anti- PCR and Western blotting were then used to assess alterations in body was purchased from BD Biosciences and used at a dilution of Nischarin at the mRNA and protein levels. 1:200. Slides were scored on the basis of average staining intensity by two pathologists individually. The criteria were as follows: Loss of heterozygosity analysis 0, no expression (negative staining); 1, weak (1%–25% positive); LOH analysis was performed using three microsatellite markers 2, moderate (26%–50% positive); 3, strong (>50% positive). (D3S3026, D3S3561, and D3S3688) with primers described in Table 1. The PCR products were loaded and separated on 7.5% polyacrylamide gels, and the allelic loss was determined Cell culture and reagents by ethidium bromide staining. Human ovarian cancer cell lines were obtained as follows: SKOV3 and IGROV were from the ATCC, A2780 from the Euro- Western blot analysis pean Collection of Cell Cultures, HO8910 from the Cell Bank of Total protein was extracted from cells using RIPA (Thermo the Chinese Academy of Sciences (CBCAS), and HEY was the kind Fisher Scientific). Equivalent amounts of protein were separated gift from Dr. Chunxiao Zhou (School of Medicine, University of on SDSPAGE gels (8% for Nischarin and 12% for other proteins) North Carolina at Chapel Hill, Chapel Hill, NC). In September of and transferred to polyvinylidene difluoride membranes. After 2013 and 2014, all working cell lines were authenticated using incubation with appropriate primary and secondary antibodies, short tandem repeat DNA profiling at CBCAS. Cell lines were the specific protein bands were visualized using a commercial ECL maintained at 37 C in a humidified atmosphere of 5% CO with 2 Chemiluminescent Kit (Beyotime). The following antibodies
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