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// Xue-feng Yang 1 , Zhi-juan Zhao 1 , Jia-jie Liu 1 , Xiang-hong Yang 2 , Yang Gao 1 , Shuang Zhao 1 , Shuai Shi 1 , Ke-qiang Huang 3 , Hua-chuan Zheng 1, 4 1 Cancer Center, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121001, China 2 Department of Pathology, Shengjing Hospital of China Medical University, Shenyang 110004, China 3 Department of Stomatology, The Second Affiliated Hospital of Jinzhou Medical University, Jinzhou 121001, China 4 Life Science Institute of Jinzhou Medical University, Jinzhou 121001, China Correspondence to: Hua-chuan Zheng, email: zheng_huachuan@hotmail.com Keywords: glioma, suberoylanilide hydroxamic acid, histone acetylation, MG132, chemotherapy Received: August 23, 2016 Accepted: November 15, 2016 Published: November 29, 2016 ABSTRACT To elucidate the anti-tumor effects and molecular mechanisms of SAHA (a histone deacetylase inhibitor) and MG132 (a proteasome inhibitor) on the aggressive phenotypes of glioma cells, we treated U87 and U251 cells with SAHA or/and MG132, and detected phenotypes’ assays with phenotype-related molecules examined. It was found that SAHA or/and MG132 treatment suppressed proliferation in both concentration- and time-dependent manners, inhibited energy metabolism, migration, invasion and lamellipodia formation, and induced G 2 arrest and apoptosis in the glioma cells. The treatment with SAHA increased the expression of acetyl-histones 3 and 4, which were recruited to the promoters of p21, p27, Cyclin D1, c-myc and Nanog to down-regulate their transcriptional levels. Expression of acetyl-histones 3 and 4 was higher in gliomas than normal brain tissues. Both drugs’ exposure suppressed tumor growth in nude mice by inducing apoptosis and inhibiting proliferation, but increased serum aminotransferase and creatinine. These results indicated that SAHA and/or MG132 may suppress the aggressive phenotypes of glioma cells. They might be employed to treat the glioma if both hepatic and renal injuries are prevented.

// Hang Lu 1 , Xue-feng Yang 1 , Xiao-qing Tian 1 , Shou-long Tang 1 , Lian-qian Li 2 , Shuang Zhao 1 , Hua-chuan Zheng 1, 3 1 Cancer Center, The Key Laboratory of Brain and Spinal Cord Injury of Liaoning Province, and Laboratory Animal Center, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China 2 Department of Surgery, Panjin Central Hospital, Panjin, China 3 Life Science Institute of Jinzhou Medical University, Jinzhou, China Correspondence to: Hua-chuan Zheng, email: zheng_huachuan@hotmail.com Keywords: gastric cancer, suberoylanilide hydroxamic acid, MG132, aggressive phenotypes, chemotherapy Received: April 17, 2016 Accepted: June 03, 2016 Published: July 18, 2016 ABSTRACT Here, we found that both SAHA and MG132 synergistically inhibited proliferation, glycolysis and mitochondrial oxidization, induced cell cycle arrest and apoptosis in MGC-803 and MKN28 cells. SAHA increased cell migration and invasionat a low concentration. SAHA induced the overexpression of acetyl histone 3 and 4, which were recruited to p21 , p27 , Cyclin D1 , c-myc and nanog promoters to transcriptionally up-regulate the former two and down-regulate the latter three. The expression of acetyl-histone 3 and 4 was increased during gastric carcinogenesis and positively correlated with cancer differentiation. SAHA and MG132 exposure suppressed tumor growth by inhibiting proliferation and inducing apoptosis in nude mice, increased serum ALT and AST levels and decreased hemaglobin level, white blood cell and neutrophil numbers. These data indicated that SAHA and MG132 in vivo and vitro synergistically induced cytotoxicity and apoptosis, suppressed proliferation, growth, migration and invasion of gastric cancer cells. Therefore, they might potentially be employed as chemotherapeutic agents if the hepatic injury and the killing effects of peripheral blood cells are avoided or ameliorated.

// Shuang Zhao 1 , Shu-rui Chen 2 , Xue-feng Yang 1 , Dao-fu Shen 1 , Yasuo Takano 3 , Rong-jian Su 4 , Hua-chuan Zheng 1, 4 1 Cancer Center, Key Laboratory of Brain and Spinal Cord Injury of Liaoning Province, and Animal Center, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China 2 Department of Science and Technology, Jinzhou Medical University, Jinzhou, China 3 School of Health Science, Tokyo University of Technology, Nishi-Kamata, Ohta-ku, Tokyo, Japan 4 Life Science Institute of Jinzhou Medical University, Jinzhou, China Correspondence to: Hua-chuan Zheng, email: zheng_huachuan@hotmail.com Keywords: colorectal cancer, BTG1, carcinogenesis, aggressive phenotypes, gene therapy Received: April 02, 2016 Accepted: June 03, 2016 Published: July 18, 2016 ABSTRACT Here, BTG1 overexpression inhibited proliferation, induced differentiation, autophagy, and apoptosis in colorectal cancer cells (p

// Shuang Zhao 1 , Xue-feng Yang 1 , Dao-fu Shen 1 , Yang Gao 1 , Shuai Shi 1 , Ji-cheng Wu 1 , Hong-xu Liu 2 , Hong-zhi Sun 1 , Rong-jian Su 3 , Hua-chuan Zheng 1, 3 1 Cancer Center, Key Laboratory of Brain and Spinal Cord Injury of Liaoning Province, and Animal Center, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121001, China 2 Department of Thoracic Surgery, The First Affiliated Hospital of China Medical University, Shenyang, 110001, China 3 Life Science Institute of Jinzhou Medical University, Jinzhou, 121001, China Correspondence to: Hua-chuan Zheng, email: zheng_huachuan@hotmail.com Keywords: lung cancer, ING5, pathogenesis, aggressiveness, prognosis Received: February 06, 2016 Accepted: May 28, 2016 Published: July 09, 2016 ABSTRACT ING5 can interact with p53, thereby inhibiting cell growth and inducing apoptosis. We found that ING5 overexpression not only inhibited proliferation, migration, and invasion, but also induced G2 arrest, differentiation, autophagy, apoptosis, glycolysis and mitochondrial respiration in lung cancer cells. ING5 transfection up-regulated the expression of Cdc2, ATG13, ATG14, Beclin-1, LC-3B, AIF, cytochrome c, Akt1/2/3, ADFP, PFK-1 and PDPc, while down-regulated the expression of Bcl-2, XIAP, survivin,β-catenin and HXK1. ING5 transfection desensitized cells to the chemotherapy of MG132, paclitaxel, and SAHA, which paralleled with apoptotic alteration. ING5 overexpression suppressed the xenograft tumor growth by inhibiting proliferation and inducing apoptosis. ING5 expression level was significantly higher in normal tissue than that in lung cancer at both protein and mRNA levels. Nuclear ING5 expression was positively correlated with ki-67 expression and cytoplasmic ING5 expression. Cytoplasmic ING5 expression was positively associated with lymph node metastasis, and negatively with age, lymphatic invasion or CPP32 expression. ING5 expression was different in histological classification: squamous cell carcinoma > adenocarcinoma > large cell carcinoma > small cell carcinoma. Taken together, our data suggested that ING5 downregulation might involved in carcinogenesis, growth, and invasion of lung cancer and could be considered as a promising marker to gauge the aggressiveness of lung cancer. It might be employed as a potential target for gene therapy of lung cancer.

Here, we found that ING5 overexpression increased autophagy, differentiation, and decreased proliferation, apoptosis, migration, invasion and lamellipodia formation in gastric cancer cells, while ING5 knockdown had the opposite effects. In SGC-7901 transfectants, ING5 overexpression caused G1 arrest, which was positively associated with 14-3-3 overexpression, Cdk4 and c-jun hypoexpression. The induction of Bax hypoexpression, Bcl-2, survivin, 14-3-3, PI3K, p-Akt and p70S6K overexpression by ING5 decreased apoptosis in SGC-7901 cells. The hypoexpression of MMP-9, MAP1B and flotillin 2 contributed to the inhibitory effects of ING5 on migration and invasion of SGC-7901 cells. ING5 overexpression might activate both β-catenin and NF-κB pathways in SGC-7901 cells, and promote the expression of down-stream genes (c-myc, VEGF, Cyclin D1, survivin, and interleukins). Compared with the control, ING5 transfectants displayed drug resistance to triciribine, paclitaxel, cisplatin, SAHA, MG132 and parthenolide, which was positively related to their apoptotic induction and the overexpression of chemoresistance-related genes (MDR1, GRP78, GRP94, IRE, CD147, FBXW7, TOP1, TOP2, MLH1, MRP1, BRCP1 and GST-π). ING5 expression was higher in gastric cancer than matched mucosa. It was inversely associated with tumor size, dedifferentiation, lymph node metastasis and clinicopathological staging of cancer. ING5 overexpression suppressed growth, blood supply and lung metastasis of SGC-7901 cells by inhibiting proliferation, enhancing autophagy and apoptosis in xenograft models. It was suggested that ING5 expression might be employed as a good marker for gastric carcinogenesis and subsequent progression by inhibiting proliferation, growth, migration, invasion and metastasis. ING5 might induce apoptotic and chemotherapeutic resistances of gastric cancer cells by activating β-catenin, NF-κB and Akt pathways.