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// Yan Jia 1, 2, * , Baoping Cao 1, 3, * , Yunsheng Yang 1 , Enqiang Linghu 1 , Qimin Zhan 4 , Youyong Lu 5 , Yingyan Yu 6 , James G. Herman 7 , Mingzhou Guo 1 1 Department of Gastroenterology & Hepatology, Chinese PLA General Hospital, Beijing 100853, China 2 Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, and Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China 3 Medical College of NanKai University, Tianjin 300071, China 4 State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China 5 Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital/Institute, Beijing 100142, China 6 Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200240, China 7 The Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA * These authors have contributed equally to this work Correspondence to: Mingzhou Guo, e-mail: mzguo@hotmail.com James G. Herman, e-mail: Hermanj3@upmc.edu Keywords: NKD1, NKD2, SOX18, DNA methylation, gastric cancer Received: April 23, 2015 Accepted: September 02, 2015 Published: September 14, 2015 ABSTRACT Naked cuticle homolog2 ( NKD2 ) is located in chromosome 5p15.3, which is frequently loss of heterozygosity in human colorectal and gastric cancers. In order to understand the mechanism of NKD2 in gastric cancer development, 6 gastric cancer cell lines and 196 cases of human primary gastric cancer samples were involved. Methylation specific PCR (MSP), gene expression array, flow cytometry, transwell assay and xenograft mice model were employed in this study. The expression of NKD1 and NKD2 was silenced by promoter region hypermethylation. NKD1 and NKD2 were methylated in 11.7% (23/196) and 53.1% (104/196) in human primary gastric cancer samples. NKD2 methylation is associated with cell differentiation, TNM stage and distant metastasis significantly (all P < 0.05), and the overall survival time is longer in NKD2 unmethylated group compared to NKD2 methylated group ( P < 0.05). Restoration of NKD2 expression suppressed cell proliferation, colony formation, cell invasion and migration, induced G2/M phase arrest, and sensitized cancer cells to docetaxel. NKD2 inhibits SOX18 and MMP-2,7,9 expression and suppresses BGC823 cell xenograft growth. In conclusion, NKD2 methylation may serve as a poor prognostic and chemo-sensitive marker in human gastric cancer. NKD2 impedes gastric cancer metastasis by inhibiting SOX18.

The activity of the Wnt pathway undergoes complex regulation to ensure proper functioning of this principal signaling mechanism during development of adult tissues. The regulation may occur at several levels and includes both positive and negative feedback loops. In the present study we employed one of such negative feedback regulators, naked cuticle homolog 1 (Nkd1), to follow the Wnt pathway activity in the intestine and liver and in neoplasia originated in these organs. Using lineage tracing in transgenic mice we localized Nkd1 mRNA to the bottom parts of the small intestinal crypts and hepatocytes surrounding the central vein of the hepatic lobule. Furthermore, in two mouse models of intestinal tumorigenesis, Nkd1 expression levels were elevated in tumors when compared to healthy tissue. We utilized a collection of human intestinal polyps and carcinomas to confirm that NKD1 represents a robust marker of neoplastic growth. In addition, expression analysis of NKD1 in liver cancer showed that high expression levels of the gene distinguish a subclass of hepatocellular carcinomas related to aberrant Wnt signaling. Finally, our results were confirmed by bioinformatic analysis of large publicly available datasets that included gene expression profiling and high-throughput sequencing data of human colon and liver cancer specimens.

// Han Guan 1, 2, * , Chunhui Liu 1, 2, * , Fang Fang 3, * , Yeqing Huang 1, 2, * , Tao Tao 1, 2 , Zhixin Ling 1, 2 , Zonghao You 1, 2 , Xu Han 1, 2 , Shuqiu Chen 1, 2 , Bin Xu 1, 2 , Ming Chen 1, 2 1 Department of Urology, Affiliated Zhongda Hospital of Southeast University, Nanjing, China 2 Surgical Research Center, Institute of Urology, Medical School, Nanjing, China 3 Department of Immunology, Bengbu Medical College, Bengbu, China * These authors contributed equally to this work Correspondence to: Bin Xu, email: njxb1982@126.com Ming Chen, email: mingchenseu@126.com Keywords: miR-744, prostate cancer, Wnt/β-catenin signaling, NKD1, tumorigenesis Received: October 21, 2016 Accepted: January 09, 2017 Published: January 18, 2017 ABSTRACT Accumulated evidence indicate that miR-744 functions as either tumor suppressor or oncogene in the progression of a variety of tumors, with a tumor type-specific way. However, little is known about how miR-744 impacts on the tumorigenesis of human prostate cancer. In this study, employing the analyses of microarray, qRT-PCR and re-analysis of MSKCC data, we found that CRPC tissues expressed much more miR-744 than ADPC tissues did, and the expression level of miR-744 was inversely associated with survival of CRPC patients. In vitro studies revealed that miR-744 promotes PCa cells proliferation, enhances migration, invasion; in vivo results demonstrated that silencing of miR-744 mediated by shRNA dramatically reduces PCa xenograft tumor growth. Importantly, through human gene expression array, pathway enrichment analysis and Western blot, we identified that miR-744 dramatically activated Wnt/β-catenin pathway by targeting multiple negative regulators of Wnt/β-catenin signaling, including SFRP1, GSK3β, TLE3 and NKD1. At molecular level, we further defined that NKD1 is a major functional target of miR-744. Our findings indicate that miR-744 acts as one of oncogenic factor in the progression of CRPC by recruiting a mechanism of aberrant activation of Wnt/β-catenin signaling.