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Fascin is a FSCN1-encoded actin bundling protein, and positively associated with proliferation, migration and metastasis of malignancies. Here, we performed a systematic meta and bioinformatics analysis through multiple online databases up to March 14, 2017. We found up-regulated fascin expression in gastric cancer, compared with normal mucosa (p

Here, we found that ING5 overexpression suppressed cell viability, glucose metabolism, migration, invasion and epithelial-mesenchymal transition, and induced cell arrest, apoptosis, senescence, autophagy and fat accumulation in ovarian cancer cells. ING5-mediated chemoresistance was positively linked to apoptotic resistance and chemoresistance-related gene expression. ING5 overexpression suppressed tumor growth of ovarian cancer by decreasing proliferation, and inducing apoptosis and autophagy. ING5 mRNA level was lower in ovarian cancer than normal ovary, and borderline than benign tumors (p < 0.05), and negatively correlated with vascular invasion, lymphatic invasion and FIGO staging of ovarian cancer (p < 0.05). ING5 protein was less expressed in primary cancer than normal ovary (p < 0.05). There was a negative correlation between ING5 mRNA expression and the overall or progression-free survival time of the cancer patients with Grade 2, Grade 3, and stage I cancer (p < 0.05). Immunohistochemically, ING5 was less expressed in serous and mucinous adenocarcinoma than miscellaneous subtypes, and positively correlated with dedifferentiation and ki-67 expression of ovarian cancer (p < 0.05). These data suggested that down-regulated ING5 expression might be involved in ovarian carcinogenesis possibly by suppressing aggressive phenotypes, including proliferation, tumor growth, migration, invasion, and anti-apoptosis.

// Hua-Chuan Zheng 1 , Bao-Cheng Gong 1 and Shuang Zhao 1 1 Department of Experimental Oncology and Animal Center, Shengjing Hospital of China Medical University, Shenyang 110004, China Correspondence to: Hua-Chuan Zheng, email: zheng_huachuan@hotmail.com Keywords: GRP78, gastric cancer, meta analysis, bioinformatics analysis Received: July 05, 2017 Accepted: August 04, 2017 Published: August 18, 2017 ABSTRACT GRP78 is a molecular chaperone located in endoplasmic reticulum, and induces folding and assembly of newly-synthesized proteins, proteasome degradation of aberrant proteins, and translocation of secretory proteins, autophagy, and epithelial-mesenchymal transition. We performed a systematic meta- and bioinformatics analysis through multiple online databases up to March 14, 2017. It was found that up-regulated GRP78 expression in gastric cancer, compared with normal mucosa at both protein and mRNA levels ( p < 0.05). GRP78 expression was positively correlated with depth of invasion, TNM staging and dedifferentiation of gastric cancer ( p < 0.05), while its mRNA expression was negatively correlated with depth of invasion, histological grading and dedifferentiation ( p < 0.05). A positive association between GRP78 expression and unfavorable overall survival was found in patients with gastric cancer ( p < 0.005). A higher GRP78 mRNA expression was positively correlated with overall and progression-free survival rates of all cancer patients, even stratified by aggressive parameters, or as an independent factor ( p < 0.05). These findings indicated that GRP78 expression might be employed as a potential marker to indicate gastric carcinogenesis and subsequent progression, even prognosis.

// Hua-Chuan Zheng 1 and Bao-Cheng Gong 1 1 Department of Experimental Oncology and Animal Center, Shengjing Hospital of China Medical University, Shenyang 110004, China Correspondence to: Hua-Chuan Zheng, email: zheng_huachuan@hotmail.com Keywords: maspin, gastric cancer, meta analysis, bioinformatics analysis Received: March 31, 2017 Accepted: August 02, 2017 Published: August 11, 2017 ABSTRACT Maspin is a mammary serine protease inhibitor that is encoded by human SERPINB5 gene, and inhibits invasion and metastasis of cancer cells as a tumor suppressor. We performed a systematic meta- and bioinformatics analysis through multiple online databases up to Feb 10, 2017. We found down-regulated maspin expression in gastric cancer, compared with normal mucosa and dysplasia ( p < 0.05). Maspin expression was negatively correlated with depth of invasion, TNM staging and dedifferentiation of gastric cancer ( p < 0.05). Nuclear maspin expression was higher in intestinal- than diffuse-type carcinoma ( p < 0.05). An inverse association between maspin expression and unfavorable overall survival was found in patients with gastric cancer ( p < 0.005). According to bioinformatics databases, SERPINB5 mRNA expression was higher in gastric cancer than normal tissues ( p < 0.05), and negatively correlated with depth of invasion, TNM staging and dedifferentiation of gastric cancer ( p < 0.05). According to KM plotter, we found that a higher SERPINB5 expression was positively correlated with overall and progression-free survival rates of all cancer patients, even stratified by aggressive parameters ( p < 0.05). These findings indicated that maspin expression might be employed as a potential marker to indicate gastric carcinogenesis, subsequent progression, and even prognosis.

// Hua-Chuan Zheng 1 and Bao-Cheng Gong 1 1 Department of Experimental Oncology and Animal Center, Shengjing Hospital of China Medical University, Shenyang 110004, China Correspondence to: Hua-Chuan Zheng, email: zheng_huachuan@hotmail.com Keywords: CD147, gastric cancer, meta analysis, bioinformatics analysis Received: June 01, 2017 Accepted: July 26, 2017 Published: August 09, 2017 ABSTRACT CD147 (also named as Basigin or EMMPRIN) might promote cancer invasion and metastasis by inducing MMP and VEGF synthesis in tumor microenvironment. We performed a systematic meta and bioinformatics analysis through multiple online databases up to March 14, 2017. Up-regulated CD147 expression was found in gastric cancer, compared with normal mucosa ( p < 0.05). The male patients with gastric cancer showed higher CD147 expression than the female ones ( p < 0.0001). CD147 expression was positively correlated with tumor size, depth of invasion, lymph node metastasis, TNM staging and unfavorable prognosis of gastric cancer ( p < 0.05). At mRNA level, CD147 expression was higher in intestinal-type and mixed-type gastric carcinomas than normal tissues ( p < 0.05). CD147 mRNA expression was negatively associated with histological grading and dedifferentiation of gastric cancer ( p < 0.05). A higher CD147 mRNA expression was negatively correlated with overall and progression-free survival rates of all cancer patients, even stratified by clinicopathological features ( p < 0.05). These findings indicated that CD147 expression might be employed as a potential marker to indicate gastric carcinogenesis and subsequent progression, even prognosis.

CDC73 interacts with human PAF1 complex, histone methyltransferase complex and RNA polymerase II for transcription elongation and 3' end processing. Its down-regulated expression was immunohistochemically detected in gastric, colorectal, ovarian and head and neck cancers, and positively correlated with aggressive behaviors and unfavorable prognosis of malignancies. We performed a bioinformatics analysis by using Oncomine, TCGA and KM plotter databases. It was found that CDC73 mRNA was overexpressed in gastric, lung, breast and ovarian cancers, even stratified by histological subtypes (p

// Hua-Chuan Zheng 1 1 Department of Experimental Oncology and Animal Center, Shengjing Hospital of China Medical University, Shenyang 110004, China Correspondence to: Hua-Chuan Zheng, email: zheng_huachuan@hotmail.com Keywords: cancer, chemoresistance, molecular mechanisms, chemotherapy Received: March 31, 2017 Accepted: June 24, 2017 Published: July 06, 2017 ABSTRACT Overcoming intrinsic and acquired drug resistance is a major challenge in treating cancer patients because chemoresistance causes recurrence, cancer dissemination and death. This review summarizes numerous molecular aspects of multi-resistance, including transporter pumps, oncogenes (EGFR, PI3K/Akt, Erk and NF-κB), tumor suppressor gene (p53), mitochondrial alteration, DNA repair, autophagy, epithelial-mesenchymal transition (EMT), cancer stemness, and exosome. The chemoresistance-related proteins are localized to extracellular ligand, membrane receptor, cytosolic signal messenger, and nuclear transcription factors for various events, including proliferation, apoptosis, EMT, autophagy and exosome. Their cross-talk frequently appears, such as the regulatory effects of EGFR-Akt-NF-κB signal pathway on the transcription of Bcl-2, Bcl-xL and survivin or EMT-related stemness. It is essential for the realization of the target, individualized and combine therapy to clarify these molecular mechanisms, explore the therapy target, screen chemosensitive population, and determine the efficacy of chemoreagents by cell culture and orthotopic model.

// Xiao-Qing Ding 1 , Shuang Zhao 1 , Lei Yang 1 , Xin Zhao 1 , Gui-Feng Zhao 1 , Shu-Peng Zhao 2 , Zhi-Jie Li 1 and Hua-Chuan Zheng 1 1 Department of Experimental Oncology and Animal Center, Shengjing Hospital of China Medical University, Shenyang 110004, China 2 Department of Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121001, China Correspondence to: Hua-Chuan Zheng, email: zheng_huachuan@hotmail.com Keywords: breast cancer, ING5, pathogenesis, aggressiveness, progression Received: January 16, 2017 Accepted: May 03, 2017 Published: May 17, 2017 ABSTRACT Here, we found that ING5 overexpression resulted in a lower proliferation, reduced glucose metabolism, S arrest, decreased migration and invasion, apoptotic induction, fat accumulation, autophagy, senescence and mesenchymal-epithelial–transition of breast cancer cells. It also suppressed the tumor growth of breast cancer cells by inhibiting proliferation, inducing apoptosis and autophagy. ING5-mediated chemoresistance was positively linked to Akt and NF-κB activation, MRP1 and GST-π overexpression, and FBXW7 hypoexpression. ING5 expression was higher in breast cancer than normal tissue at both mRNA and protein levels. ING5 mRNA expression was positively correlated with relapse- and distant metastasis-free survival rates. Nuclear ING5 expression showed gradual decrease from breast normal tissue, fibroadenoma, adenomatosis, primary to metastatic cancers, while versa for cytoplasmic ING5. Nuclear ING5 expression was negatively correlated with distant metastasis and p53 hypoexpression, while cytoplasmic ING5 expression was positively correlated with tumor size and ER expression. These data suggested that up-regulated expression and nucleocytoplasmic translocation of ING5 protein were observed in breast cancer. The higher expression of nuclear ING5 was inversely linked to worse clinicopathological behaviors of breast cancer by in vivo and vitro reversing aggressive phenotypes. Therefore, it should be employed as a biomarker to indicate the tumorigenesis and aggressiveness of breast cancer, and as a potential target for gene therapy.

To elucidate the anti-tumor effects and molecular mechanisms of ING5 on glioma cells, we overexpressed it in U87 cells, and examined the phenotypes and their relevant molecules. It was found that ING5 overexpression suppressed proliferation, energy metabolism, migration, invasion, and induced G2/M arrest, apoptosis, dedifferentiation, senescence, mesenchymal- epithelial transition and chemoresistance to cisplatin, MG132, paclitaxel and SAHA in U87 cells. There appeared a lower expression of N-cadherin, Twist, Slug, Zeb1, Zeb2, Snail, Ac-H3, Ac-H4, Cdc2, Cdk4 and XIAP, but a higher expression of Claudin 1, Histones 3 and 4, p21, p53, Bax, β-catenin, PI3K, Akt, and p-Akt in ING5 transfectants. ING5 overexpression suppressed tumor growth of U87 cells in nude mice by inhibiting proliferation and inducing apoptosis. Down-regulated ING5 expression was closely linked to the tumorigenesis and histogenesis of glioma. These data indicated that ING5 expression might be considered as a good marker for the tumorigenesis and histogenesis of gliomas. It might be employed as a potential target for gene therapy of glioma. PI3K/Akt or β-catenin/TCF-4 activation might be positively linked to chemotherapeutic resistance, mediated by ING5.

// Gui-Feng Zhao 1 , Shuang Zhao 1 , Jia-Jie Liu 1 , Ji-Cheng Wu 1 , Hao-Yu He 1 , Xiao-Qing Ding 1 , Xue-Wen Yu 2 , Ke-Qiang Huang 2 , Zhi-Jie Li 1 , Hua-Chuan Zheng 1 1 Department of Experimental Oncology and Animal Center, Shengjing Hospital of China Medical University, Shenyang 110004, China 2 Office of Administration, Jinzhou Medical University, Jinzhou 121001, China Correspondence to: Hua-Chuan Zheng, email: zheng_huachuan@hotmail.com Keywords: Cre recombinase, transgenic mouse, cytokeratin 19, PTEN, carcinogenesis Received: December 01, 2016 Accepted: January 11, 2017 Published: February 17, 2017 ABSTRACT Cytokeratin 19 (K19) is expressed in various differentiated cells, including gastric, intestinal and bronchial epithelial cells, and liver duct cells. Here, we generated a transgenic mouse line, K19-Cre, in which the expression of Cre recombinase was controlled by the promoter of K19. To test the tissue distribution and excision activity of Cre recombinase, K19-Cre transgenic mice were bred with Rosa26 reporter strain and a mouse strain that carries PTEN conditional alleles (PTEN Loxp/Loxp ). At mRNA level, Cre was strongly expressed in the stomach, lung and intestine, while in stomach, lung, and liver at protein level. The immunoreactivity to Cre was strongly observed the cytoplasm of gastric, bronchial and intestinal epithelial cells. Cre activity was detectable in gastric, bronchial and intestinal epithelial cells, according to LacZ staining. In K19-Cre/PTEN Loxp/Loxp mice, PTEN was abrogated in stomach, intestine, lung, liver and breast, the former two of which were verified by in situ PCR. There appeared breast cancer with PTEN loss. These data suggest that K19 promoter may be a useful tool to study the pathophysiological functions of cytokeratin 19-positive cells, especially gastrointestinal epithelial cells. Cell specificity of neoplasia is not completely attributable to the cell-specific expression of oncogenes and cell-specific loss of tumor suppressor genes.

// Hua-Chuan Zheng 1 , Hao-Yu He 1 , Ji-Cheng Wu 1 , Jing Li 2 , Shuang Zhao 1 , Gui-Feng Zhao 1 , Hua-Mao Jiang 2 , Xue-Wen Yu 2 , Zhi-Jie Li 1 1 Department of Experimental Oncology and Animal Center, Shengjing Hospital of China Medical University, Shenyang 110004, China 2 Jinzhou Medical University, Jinzhou 121001, China Correspondence to: Hua-Chuan Zheng, email: zheng_huachuan@hotmail.com Keywords: colorectal cancer, BTG3, pathobiological behaviors, aggressive phenotypes, gene therapy Received: December 06, 2016 Accepted: January 11, 2017 Published: February 17, 2017 ABSTRACT Here, we found that down-regulated expression of BTG3 might be positively correlated with colorectal carcinogenesis and its overexpression suppressed proliferation, glycolysis, mitochondrial respiration, cell cycle progression, migration, and invasion, and induced apoptosis, senescence and differentiation in SW480 and SW620 cells. After treated with cisplatin, MG132, paclitaxel and SAHA, BTG3 transfectants exhibited lower viability and higher apoptosis than the control in both time- and dose-dependent manners. BTG3 overexpression up- regulated the protein expression of Cyclin E, p16, p27, NF-κB, p38α/β, XIAP, Bcl-2, ATG14 and p53, but down-regulated the mRNA expression of MRP1 , BCRP , and mTOR in SW480 and SW620 cells. BTG3 overexpression inhibited tumor growth of SW620 cells by suppressing proliferation and inducing apoptosis. It was suggested that down-regulated BTG3 expression might be considered as a marker for colorectal carcinogenesis. BTG3 overexpression might reverse the aggressive phenotypes and be employed as a potential target for gene therapy of colorectal cancer.

// 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.

// Yang Gao 1, * , Ji-feng Zhang 1, * , Qing-chang Li 2 , Jia-jie Liu 1 , Li-li Liu 1 , Xue-feng Yang 1 , Hua-mao Jiang 3 , 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 121001, China 2 Department of Pathology, The First Affiliated Hospital of China Medical University, Shenyang 110001, China 3 Department of Urology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121001, China 4 Life Science Institute of Jinzhou Medical University, Jinzhou 121001, China * These authors have contributed equally to this work Correspondence to: Hua-chuan Zheng, email: zheng_huachuan@hotmail.com Keywords: lung cancer, clinicopathological behaviors, prognosis, China, Japan Received: May 29, 2016 Accepted: August 21, 2016 Published: September 06, 2016 ABSTRACT Here, we retrospectively compared the differences in clinicopathological behaviors and prognosis of lung cancer from the First Affiliated Hospital (CMU1, n=513), Shengjing Hospital (CMUS, n=1021), Tumor Hospital (CMUT, n=5378) of China Medical University, the First Affiliated Hospital of Dalian (DMU, n=2251) and Jinzhou (JMU, n=630) Medical University, Takaoka Kouseiren Hospital (Takaoka, n=163) of Japan. Japanese lung cancer patients showed smaller tumor size, lower TNM staging, lower ratio of squamous cell carcinoma and higher ratio of small and large cell carcinomas than Chinese patients (p

// 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.

5-FU is a common first-line chemotherapeutic drug for the treatment of hepatocellular carcinoma. However the development of acquired resistance to 5-FU confines its clinical usages. Although this phenomenon has been the subject of intense investigation, the exact mechanism of acquired resistance to 5-FU remains elusive. Here, we report that over-expression of GRP78 contributes to acquired resistance to 5-FU in HCC by up-regulating the c-Src/LSF/TS axis. Moreover, we found that the resistance to 5-FU conferred by GRP78 is mediated by its ATPase domain. The ATPase domain differentially increased the expression of LSF, TS and promoted the phosphorylation of ERK and Akt. We further identified that GRP78 interacts physically with c-Src through its ATPase domain and promotes the phosphorylation of c-Src, which in turn increases the expression of LSF in the nucleus. Together, GRP78 confers the resistance to 5-FU by up-regulating the c-Src/LSF/TS axis via its ATPase domain.

// Hua-chuan Zheng 1 , Jing Li 2 , Dao-fu Shen 1 , Xue-feng Yang 1 , Shuang Zhao 1 , Ya-zhou Wu 1 , Yasuo Takano 3 , Hong-zhi Sun 1 , Rong-jian Su 4 , Jun-sheng Luo 1 , Wen-feng Gou 1 1 Cancer Research Center, Key Laboratory of Brain and Spinal Cord Injury of Liaoning Province, and Laboratory Animal Center, The First Affiliated Hospital of Liaoning Medical University, Jinzhou, China 2 Department of Gastroenterology, The First Affiliated Hospital of Liaoning Medical University, Jinzhou, China 3 School of Health Science, Tokyo University of Technology, Ohta-ku, Tokyo, Japan 4 Experimental Center, Liaoning Medical University, Jinzhou, China Correspondence to: Wen-feng Gou, e-mail: xiaogouaeiou@163.com Keywords: gastric cancer, BTG1, pathobiological behaviors, carcinogenesis, gene therapy Received: March 11, 2015 Accepted: May 23, 2015 Published: June 05, 2015 ABSTRACT Here, we found that BTG1 overexpression inhibited proliferation, migration and invasion, induced G 2 /M arrest, differentiation, senescence and apoptosis in BGC-823 and MKN28 cells ( p < 0.05). BTG1 transfectants showed a higher mRNA expression of Cyclin D1 and Bax , but a lower mRNA expression of cdc2, p21, mTOR and MMP-9 than the control and mock ( p < 0.05). After treated with cisplatin, MG132, paclitaxel and SAHA, both BTG1 transfectants showed lower mRNA viability and higher apoptosis than the control in both time- and dose-dependent manners ( p < 0.05) with the hypoexpression of chemoresistance-related genes ( slug , CD147 , GRP78 , GRP94 , FBXW7 TOP1 , TOP2 and GST-π ). BTG1 expression was restored after 5-aza-2′-deoxycytidine treatment in gastric cancer cells. BTG1 expression was statistically lower in gastric cancer than non-neoplastic mucosa and metastatic cancer in lymph node ( p < 0.05). BTG1 expression was positively correlated with depth of invasion, lymphatic and venous invasion, lymph node metastasis, TNM staging and worse prognosis ( p < 0.05). The diffuse-type carcinoma showed less BTG1 expression than intestinal- and mixed-type ones ( p < 0.05). BTG1 overexpression suppressed tumor growth and lung metastasis of gastric cancer cells by inhibiting proliferation, enhancing autophagy and apoptosis in xenograft models. It was suggested that down-regulated BTG1 expression might promote gastric carcinogenesis partially due to its promoter methylation. BTG1 overexpression might reverse the aggressive phenotypes and be employed as a potential target for gene therapy of gastric 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.

// Hua-Chuan Zheng 1 , Yu-Hong Qiu 1, 2 and Shuang Zhao 1 1 Department of Experimental Oncology and Animal Center, Shengjing Hospital of China Medical University, Shenyang 110004, China 2 Library, China Medical University, Shenyang 110004, China Correspondence to: Hua-Chuan Zheng, email: zheng_huachuan@hotmail.com Keywords: PTEN; gastric cancer; bibliometrics; meta analysis; bioinformatics analysis Received: August 01, 2017 Accepted: November 03, 2017 Published: January 02, 2018 ABSTRACT PTEN encodes a dual phospholipid phosphatase, and is frequently deleted, mutated or down-regulated in a variety of human malignancies. Here, we performed a systematic bibliometric, meta- and bioinformatics analysis through multiple online databases up to March 14, 2017. The co-citation and co-word analysis showed that the study about PTEN and gastric cancer mainly focused on PTEN discovery, correlation of its genetic and epigenetic alteration with cancers, the effects of PTEN expression on the phenotypes of gastric cancer cells, and the regulatory effects of miRNA on PTEN translation. Meta-analysis indicated that down-regulated PTEN expression was seen in gastric cancer in comparison to normal mucosa and dysplasia ( p < 0.05), and positively with depth of invasion, lymph node and distant metastasis, TNM staging, dedifferentiation and poor prognosis of gastric cancer ( p < 0.05). According to bioinformatics databases, PTEN mRNA expression was higher in gastric cancer than normal tissues ( p < 0.05), and positively correlated with depth of invasion and differentiation of gastric cancer ( p < 0.05). Kaplan-Meier plotter showed that a higher PTEN expression was positively correlated with overall and progression-free survival rates of all cancer patients, even stratified by aggressive parameters ( p < 0.05). These findings indicated that PTEN expression might be employed as a potential marker to indicate gastric carcinogenesis and subsequent progression, even prognosis.

// Hua-Chuan Zheng 1 and Li-Li Liu 2 1 Department of Experimental Oncology and Animal Center, Shengjing Hospital of China Medical University, Shenyang 110004, China 2 Department of Pathology, Harbin Medical University-Daqing, Daqing 163319, China Correspondence to: Hua-Chuan Zheng, email: zheng_huachuan@hotmail.com Keywords: FHIT, gastric cancer, meta-analysis, bioinformatics analysis Received: August 01, 2017 Accepted: October 03, 2017 Published: November 03, 2017 ABSTRACT FHIT (fragile histine triad) acts as diadenosine P1, P3-bis (5'-adenosyl)-triphosphate adenylohydrolase involved in purine metabolism, and induces apoptosis as a tumor suppressor. We performed a systematic meta- and bioinformatics analysis through multiple online databases up to March 14, 2017. The down-regulated FHIT expression was found in gastric cancer, compared with normal mucosa and dysplasia ( p < 0.05). FHIT expression was negatively with depth of invasion, lymph node metastasis, distant metastasis, TNM staging and dedifferentiation of gastric cancer ( p < 0.05). A positive association between FHIT expression and favorable overall survival was found in patients with gastric cancer ( p < 0.05). According to Kaplan-Meier plotter, we found that a higher FHIT expression was negatively correlated with overall and progression-free survival rates of all cancer patients, even stratified by aggressive parameters ( p < 0.05). These findings indicated that FHIT expression might be employed as a potential marker to indicate gastric carcinogenesis and subsequent progression, even prognosis.

// Hua-chuan Zheng 1 , Jia-jie Liu 2 , Jing Li 2 , Ji-cheng Wu 1 , Lei Yang 1 , Gui-feng Zhao 1 , Xin Zhao 1 , Hua-mao Jiang 2 , Ke-qiang Huang 2 , Zhi-jie Li 1 1 Department of Experimental Oncology and Animal Center, Shengjing Hospital of China Medical University, Shenyang 110004, China 2 Jinzhou Medical University, Jinzhou 121001, China Correspondence to: Hua-chuan Zheng, email: zheng_huachuan@hotmail.com Keywords: colorectal cancer, parafibromin, pathobiological behaviors, aggressive phenotypes, gene therapy Received: December 16, 2016 Accepted: January 24, 2017 Published: February 16, 2017 ABSTRACT Down-regulated parafibromin is positively linked to the pathogenesis of parathyroid, lung, breast, ovarian, gastric and colorectal cancers. Here, we found that wild-type (WT) parafibromin overexpression suppressed proliferation, tumor growth, induced cell cycle arrest and apoptosis in colorectal cancer cells (p

// Xue-feng Yang 1 , Ji-feng Zhang 1 , Jun-jun Li 1 , Shuang Zhao 1 , Shuai Shi 1 , Ji-cheng Wu 1 , Lei Fang 1 , Hua-mao Jiang 2 , 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 Urology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121001, China 3 Life Science Institute of Jinzhou Medical University, Jinzhou 121001, China Correspondence to: Hua-chuan Zheng, email: zheng_huachuan@hotmail.com Keywords: colorectal cancers, pathological behaviors, prognosis, China, Japan Received: May 29, 2016 Accepted: August 25, 2016 Published: September 24, 2016 ABSTRACT Here, we collected the information of 17304 and 2014 inpatients with colorectal cancer (CRC) from general hospitals of China and Japan respectively, and analyzed microscopic and macroscopic aspects, even stratified by the age and gender. It was found that Chinese CRC patients showed younger prone, more rectal and ascending cancers, less sigmoid and transverse cancers, larger size, less invasion into lymphatic system or metastasis into lymph node, and poorer differentiation than Japanese ones ( p < 0.05). TNM staging was employed as an independent factor for the prognosis of the CRC patients regardless of the country ( p < 0.05). Female patients showed larger tumor size, easier invasion and metastasis into lymphatic system, and worse differentiation than males ( p < 0.05). The younger patients displayed frequent invasion and metastasis into lymphatic system, and poor differentiation in comparison to elder ones ( p < 0.05). These findings demonstrated that Japanese patients seemed to have more invasion and metastasis due to standard and precise operation and pathological diagnosis accuracy. Actually, Chinese patients had more aggressive pathological characteristics and a poorer prognosis. Therefore, it is essential to establish a routine screening methodology, a standard treatment system and postoperative diagnosis protocol for the prevention and therapeutics of Chinese CRC patients, especially for female and young patients.

BTG (B-cell translocation gene) can inhibit cell proliferation, metastasis and angiogenesis, cell cycle progression, and induce differentiation in various cells. Here, we found that BTG3 overexpression inhibited proliferation, induced S/G2 arrest, differentiation, autophagy, apoptosis, suppressed migration and invasion in MKN28 and MGC803 cells (p < 0.05). BTG3 transfectants showed a higher mRNA expression of p27, Bax, 14-3-3, Caspase-3, Caspase-9, Beclin 1, NF-κB, IL-1, -2, -4, -10 and -17, but a lower mRNA expression of p21, MMP-9 and VEGF than the control and mock (p < 0.05). At protein level, BTG3 overexpression increased the expression of CDK4, AIF, LC-3B, Beclin 1 and p38 (p < 0.05), but decreased the expression of p21 and β-catenin in both transfectants (p < 0.05). After treated with cisplatin, MG132, paclitaxel and SAHA, both BTG3 transfectants showed lower viability and higher apoptosis than the control in both time- and dose-dependent manners (p < 0.05). BTG3 expression was restored after 5-aza-2'-deoxycytidine or MG132 treatment in gastric cancer cells. BTG3 expression was decreased in gastric cancer in comparison to the adjacent mucosa (p < 0.05), and positively correlated with venous invasion and dedifferentiation of cancer (p < 0.05). It was suggested that BTG3 expression might contribute to gastric carcinogenesis. BTG3 overexpression might reverse the aggressive phenotypes and be employed as a potential target for gene therapy of gastric cancer.

// Wen-feng Gou 1 , Shuang Zhao 1 , Dao-fu Shen 1 , Xue-feng Yang 1 , Yun-peng Liu 2 , Hong-zhi Sun 1 , Jun-sheng Luo 1 and Hua-chuan Zheng 1 1 Cancer Research Center, Key Laboratory of Brain and Spinal Cord Injury of Liaoning Province, and Laboratory Animal Center, The First Affiliated Hospital of Liaoning Medical University, Jinzhou, China 2 Department of Oncological Medicine, The First Affiliated Hospital of China Medical University, Shenyang, China Correspondence to: Hua-chuan Zheng, email: // Keywords : JC virus, T antigen, oncogenesis, transgenic mouse, lens tumor Received : January 27, 2015 Accepted : February 01, 2015 Published : March 10, 2015 Abstract JC virus (JCV), a ubiquitous polyoma virus that commonly infects the human, is identified as the etiologic agent for progressive multifocal leukoencephalopathy and some malignancies. To clarify the oncogenic role of JCV T antigen, we established two transgenic mice of T antigen using either α-crystallin A (αAT) or cytokeratin 19(KT) promoter. Lens tumors were found in high-copy αAT mice with the immunopositivity of T antigen, p53, β-catenin and N-cadherin. Enlarged eyeballs were observed and tumor invaded into the brain by magnetic resonance imaging and hematoxylin-and-eosin staining. The overall survival time of homozygous mice was shorter than that of hemizygous mice (p