Overexpression of Rho effector rhotekin confers increased survival in gastric adenocarcinoma

Ching-Ann Liu, Mei-Jung Wang, Chin-Wen Chi, Chew-Wun Wu, Jeou-Yuan Chen

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Like many epithelial-derived cancers, gastric cancer (GC) results from a multistep tumorigenic process. However, the detailed mechanisms involved in GC formation are poorly characterized. Using an ordered differential display method, we have identified rhotekin (RTKN), the gene coding for the Rho effector, RTKN, as one of the genes differentially expressed in human GC. Northern analysis using human multiple tissue blots showed that RTKN is predominantly expressed in the kidney and spinal cord, and, to a lesser degree, in the thyroid, tongue, liver, brain, prostate, trachea, and stomach. RT-PCR analysis confirmed that RTKN was overexpressed in most (5/7; 71%) GC examined. By analyzing the Stanford Microarray Database for the expression profiles of gastric tissues, we also found a progressional increase in RTKN expression in nonneoplastic mucosa, GC, and then lymph node metastases (p <0.005 by Jonckheere-Terpstra test), suggesting that RTKN expression correlates with GC progression. The role of RTKN in the pathogenic development of GC was investigated by transfection and expression of RTKN in AGS gastric cells, which express endogenous RTKN at a low basal level. Flow-cytometric analysis showed that RTKN-transfected AGS cells were significantly more resistant than vector-transfected cells to apoptosis upon treatment with sodium butyrate. To explore the mechanisms underlying RTKN-mediated cell survival, a reporter assay was performed. Since the NF-κB activation is known to promote cell survival and Rho GTPase may lead to NF-κB activation, we transfected AGS cells with the RTKN expression vector along with a pNF-κB-Luc reporter plasmid. Our results showed that overexpression of RTKN induced robust activation of NF-κB, and RTKN-mediated NF-κB activation was suppressed significantly by C3 transferase, an inhibitor of the small GTPase Rho. We conclude that Rho/RTKN-mediated NF-κB activation leading to cell survival may play a key role in gastric tumorigenesis. This study provides original documentation for the overrepresentation of the Rho GTPase effector rhotekin in human cancer and its links to cancer formation. Copyright © 2004 National Science Council, ROC and S. Karger AG, Basel.
Original languageEnglish
Pages (from-to)661-670
Number of pages10
JournalJournal of Biomedical Science
Volume11
Issue number5
DOIs
Publication statusPublished - 2004
Externally publishedYes

Fingerprint

Stomach Neoplasms
Stomach
Adenocarcinoma
Chemical activation
Survival
rho GTP-Binding Proteins
Cells
Cell Survival
Genes
Tissue
Butyric Acid
Monomeric GTP-Binding Proteins
Microarrays
Transferases
Liver
Assays
Brain
Plasmids
Display devices
Apoptosis

Keywords

  • Antiapoptosis
  • Effectors
  • Gastric cancer
  • Nuclear factor-κB
  • Rho GTPases
  • butyric acid
  • immunoglobulin enhancer binding protein
  • regulator protein
  • Rho guanine nucleotide binding protein
  • rhotekin
  • unclassified drug
  • apoptosis
  • article
  • brain
  • cancer growth
  • carcinogenesis
  • cell survival
  • controlled study
  • correlation analysis
  • data base
  • differential display
  • female
  • flow cytometry
  • gene expression profiling
  • gene expression regulation
  • gene identification
  • gene overexpression
  • genetic transfection
  • human
  • human cell
  • human tissue
  • kidney
  • liver
  • lymph node metastasis
  • male
  • Northern blotting
  • plasmid
  • priority journal
  • prostate
  • protein function
  • reverse transcription polymerase chain reaction
  • spinal cord
  • statistical significance
  • stomach
  • stomach adenocarcinoma
  • thyroid gland
  • tissue distribution
  • tongue
  • trachea
  • Adenocarcinoma
  • Base Sequence
  • Cell Survival
  • DNA Primers
  • Flow Cytometry
  • Gene Expression Profiling
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • NF-kappa B
  • Organ Specificity
  • Polymerase Chain Reaction
  • Restriction Mapping
  • Reverse Transcriptase Polymerase Chain Reaction
  • Stomach Neoplasms
  • vectors

Cite this

Overexpression of Rho effector rhotekin confers increased survival in gastric adenocarcinoma. / Liu, Ching-Ann; Wang, Mei-Jung; Chi, Chin-Wen; Wu, Chew-Wun; Chen, Jeou-Yuan.

In: Journal of Biomedical Science, Vol. 11, No. 5, 2004, p. 661-670.

Research output: Contribution to journalArticle

Liu, Ching-Ann ; Wang, Mei-Jung ; Chi, Chin-Wen ; Wu, Chew-Wun ; Chen, Jeou-Yuan. / Overexpression of Rho effector rhotekin confers increased survival in gastric adenocarcinoma. In: Journal of Biomedical Science. 2004 ; Vol. 11, No. 5. pp. 661-670.
@article{67037f999d8249ada410e50eeb02d6da,
title = "Overexpression of Rho effector rhotekin confers increased survival in gastric adenocarcinoma",
abstract = "Like many epithelial-derived cancers, gastric cancer (GC) results from a multistep tumorigenic process. However, the detailed mechanisms involved in GC formation are poorly characterized. Using an ordered differential display method, we have identified rhotekin (RTKN), the gene coding for the Rho effector, RTKN, as one of the genes differentially expressed in human GC. Northern analysis using human multiple tissue blots showed that RTKN is predominantly expressed in the kidney and spinal cord, and, to a lesser degree, in the thyroid, tongue, liver, brain, prostate, trachea, and stomach. RT-PCR analysis confirmed that RTKN was overexpressed in most (5/7; 71{\%}) GC examined. By analyzing the Stanford Microarray Database for the expression profiles of gastric tissues, we also found a progressional increase in RTKN expression in nonneoplastic mucosa, GC, and then lymph node metastases (p <0.005 by Jonckheere-Terpstra test), suggesting that RTKN expression correlates with GC progression. The role of RTKN in the pathogenic development of GC was investigated by transfection and expression of RTKN in AGS gastric cells, which express endogenous RTKN at a low basal level. Flow-cytometric analysis showed that RTKN-transfected AGS cells were significantly more resistant than vector-transfected cells to apoptosis upon treatment with sodium butyrate. To explore the mechanisms underlying RTKN-mediated cell survival, a reporter assay was performed. Since the NF-κB activation is known to promote cell survival and Rho GTPase may lead to NF-κB activation, we transfected AGS cells with the RTKN expression vector along with a pNF-κB-Luc reporter plasmid. Our results showed that overexpression of RTKN induced robust activation of NF-κB, and RTKN-mediated NF-κB activation was suppressed significantly by C3 transferase, an inhibitor of the small GTPase Rho. We conclude that Rho/RTKN-mediated NF-κB activation leading to cell survival may play a key role in gastric tumorigenesis. This study provides original documentation for the overrepresentation of the Rho GTPase effector rhotekin in human cancer and its links to cancer formation. Copyright {\circledC} 2004 National Science Council, ROC and S. Karger AG, Basel.",
keywords = "Antiapoptosis, Effectors, Gastric cancer, Nuclear factor-κB, Rho GTPases, butyric acid, immunoglobulin enhancer binding protein, regulator protein, Rho guanine nucleotide binding protein, rhotekin, unclassified drug, apoptosis, article, brain, cancer growth, carcinogenesis, cell survival, controlled study, correlation analysis, data base, differential display, female, flow cytometry, gene expression profiling, gene expression regulation, gene identification, gene overexpression, genetic transfection, human, human cell, human tissue, kidney, liver, lymph node metastasis, male, Northern blotting, plasmid, priority journal, prostate, protein function, reverse transcription polymerase chain reaction, spinal cord, statistical significance, stomach, stomach adenocarcinoma, thyroid gland, tissue distribution, tongue, trachea, Adenocarcinoma, Base Sequence, Cell Survival, DNA Primers, Flow Cytometry, Gene Expression Profiling, Humans, Intracellular Signaling Peptides and Proteins, NF-kappa B, Organ Specificity, Polymerase Chain Reaction, Restriction Mapping, Reverse Transcriptase Polymerase Chain Reaction, Stomach Neoplasms, vectors",
author = "Ching-Ann Liu and Mei-Jung Wang and Chin-Wen Chi and Chew-Wun Wu and Jeou-Yuan Chen",
note = "被引用次數:14 Export Date: 28 March 2016 CODEN: JBCIE 通訊地址: Chen, J.-Y.; Institute of Biomedical Sciences, Academia Sinica, 128 Section 2 Yen-Chiu-Yuan Road, Taipei 11529, Taiwan; 電子郵件: bmchen@ibms.sinica.edu.tw 化學物質/CAS: butyric acid, 107-92-6, 156-54-7, 461-55-2; DNA Primers; Intracellular Signaling Peptides and Proteins; NF-kappa B; RTKN protein, human 參考文獻: Bishop, A.L., Hall, A., Rho GTPases and their effector proteins (2000) Biochem J, 348, pp. 241-255; Brizzard, B.L., Chubet, R.G., Vizard, D.L., Immunoaffinity purification of FLAG epitope-tagged bacterial alkaline phosphatase using a novel monoclonal antibody and peptide elution (1994) Biotechniques, 16, pp. 730-735; Cammarano, M.S., Minden, A., Dbl and the Rho GTPases activate NF B by IBB kinase (IKK)-dependent and IKK-independent pathways (2001) J Biol Chem, 276, pp. 25876-25882; Chen, J.-Y., Funk, W.D., Wright, W.E., Shay, J.W., Minna, J.D., Heterogeneity of transcriptional activity of mutant p53 proteins and p53 DNA target sequences (1993) Oncogene, 8, pp. 2159-2166; Chuang, S.-E., Yeh, P.-Y., Lu, Y.-S., Lai, G.-M., Liao, C.-M., Gao, M., Cheng, A.-L., Basal levels and patterns of anticancer drug-induced activation of nuclear factor-kB (NF-CB), and its attenuation by tamoxifen, dexamethasone, and curcumin in carcinoma cells (2002) Biochem Pharmacol, 63, pp. 1709-1716; Clark, E.A., Golub, T.R., Lander, E.S., Hynes, R.O., Genomic analysis of metastasis reveals an essential role for RhoC (2000) Nature, 406, pp. 532-535; Del Peso, L., Hernandez-Alcoceba, R., Embade, N., Carnero, A., Esleve, P., Paje, C., Lacal, J.C., Rho proteins induce metastatic properties in vivo (1997) Oncogene, 15, pp. 3047-3057; Donovan, S., Shannon, K.M., Bollag, G., GTPase activating proteins: Critical regulators of intracellular signaling (2002) Biochim Biophys Acta, 1602, pp. 23-45; Engers, R., Zwaka, T.P., Gohr, L., Weber, A., Gerharz, C.D., Gabbert, H.E., Tiam1 mutations in human renal-cell carcinomas (2000) Int J Cancer, 88, pp. 369-376; Fritz, G., Brachetti, C., Schmidt, M., Kaina, B., Rho GTPases in human breast tumours: Expression and mutation analyses and correlation with clinical parameters (2002) Br J Cancer, 87, pp. 635-644; Fritz, G., Just, I., Kaina, B., Rho GTPases are over-expressed in human tumors (1999) Int J Cancer, 81, pp. 682-687; Fu, Q., Yu, L., Liu, Q., Zhang, J., Zhang, H., Zhao, S., Molecular cloning, expression characterization, and mapping of a novel putative inhibitor of Rho GTPase activity, RTKN, to D2S145-D2S286 (2000) Genomics, 66, pp. 328-332; Hall, A., Nobes, C.D., Rho GTPases: Molecular switches that control the organization and dynamics of the actin cytoskeleton (2000) Philos Trans R Soc Lond B Biol Sci, 355, pp. 965-970; Ikeda, H., Nagashima, K., Yanase, M., Tomiya, T., Arai, M., Inoue, Y., Tejima, K., Fujiwara, K., Involvement of Rho/Rho kinase pathway in regulation of apoptosis in rat hepatic stellate cells (2003) Am J Physiol Gastrointest Liver Physiol, 285, pp. G880-G886; Kamai, T., Arai, S., Sumi, T., Tsujii, M., Honda, T., Yamanishi, T., Yoshida, K.I., The rho/rho-kinase pathway is involved in the progression of testicular germ cell tumor (2003) BJU Int, 89, pp. 449-453; Kanai, M., Konda, Y., Nakajima, T., Izumi, Y., Takeuchi, T., Chiba, T., TGF-alpha inhibits apoptosis of murine gastric pit cells through an NF-κB-dependent pathway (2001) Gastroenterology, 121, pp. 56-67; Kaneko, K., Satoh, K., Masamune, A., Satoh, A., Shimosegawa, T., Expression of ROCK-1 in human pancreatic cancer: Its down-regulation by morpholino oligo antisense can reduce the migration of pancreatic cancer cells in vitro (2002) Pancreas, 24, pp. 251-257; Karin, M., Cao, Y., Greten, F.R., Li, Z.W., NF-kappaB in cancer: From innocent bystander to major culprit (2002) Nat Rev Cancer, 2, pp. 301-310; Kim, N.S., Lee, G.M., Inhibition of sodium butyrate-induced apoptosis in recombinant Chinese hamster ovary cells by constitutively expressing antisense RNA of caspase-3 (2002) Biotechnol Bioeng, 78, pp. 217-228; Kourlas, P.J., Strout, M.P., Becknell, B., Veronese, M.L., Croce, C.M., Theil, K.S., Krahe, R., Caligiuri, M.A., Identification of a gene at 11q23 encoding a guanine nucleotide exchange factor: Evidence for its fusion with MLL in acute myeloid leukemia (2000) Proc Natl Acad Sci USA, 97, pp. 2145-2150; Lai, J.-M., Lu, C.-Y., Yen-Yang, H.-F., Chang, Z.-F., Lysophosphatidic acid promotes phorbol-ester-induced apoptosis in TF-1 cells by interfering with adhesion (2001) Biochem J, 359, pp. 227-233; Leung, S.Y., Chen, X., Chu, K.M., Yuen, S.T., Mathy, J., Ji, J., Chan, A.S.Y., Brown, P.O., Phospholipase A2 group IIA expression in gastric adenocarcinoma is associated with prolonged survival and less frequent metastasis (2002) Proc Natl Acad Sci USA, 99, pp. 16203-16208; Matz, M., Usman, N., Shagin, D., Bogdanova, E., Lukyanov, S., Ordered differential display: A simple method for systematic comparison of gene expression profiles (1997) Nucleic Acids Res, 25, pp. 2541-2542; Metzger, E., Muller, J.M., Ferrari, S., Buettner, R., Schule, R., A novel inducible transactivation domain in the androgen receptor: Implications for PRK in prostate cancer (2003) EMBO J, 22, pp. 270-280; Olofsson, B., Rho guanine dissociation inhibitors: Pivotal molecules in cellular signaling (1999) Cell Signal, 11, pp. 545-554; Perona, R., Montaner, S., Saniger, L., Sanchez-Perez, I., Bravo, R., Lacal, J.C., Activation of the nuclear factor-2B by Rho, CDC42, and Rac-1 proteins (1997) Genes Dev, 11, pp. 463-475; Reid, T., Furuyashiki, T., Ishizaki, T., Watanabe, G., Watanabe, N., Fujisawa, K., Morii, N., Narumiya, S., Rhotekin, a new putative target for Rho bearing homology to a serine/threonine kinase, PKN, and rhophilin in the rho-binding domain (1996) J Biol Chem, 271, pp. 13556-13560; Reynaud, C., Fabre, S., Jalinot, P., The PDZ protein TIP-1 interacts with the Rho effector rhotekin and is involved in Rho signaling to the serum response element (2000) J Biol Chem, 275, pp. 33962-33968; Schmidt, A., Hall, A., Guanine nucleotide exchange factors for Rho GTPases: Turning on the switch (2002) Genes Dev, 16, pp. 1587-1609; Schnelzer, A., Prechtel, D., Knaus, U., Dehne, K., Gerhard, M., Graeff, H., Harbeck, N., Lengyel, E., Rac1 in human breast cancer: Overexpression, mutation analysis, and characterization of a new isoform, Rac1b (2000) Oncogene, 19, pp. 3013-3020; Srivastava, S.K., Wheelock, R.H., Aaronson, S.A., Eva, A., Identification of the protein encoded by the human diffuse B-cell lymphoma (dbl) oncogene (1986) Proc Natl Acad Sci USA, 83, pp. 8868-8872; Suwa, H., Ohshio, G., Imamura, T., Watanabe, G., Arii, S., Imamura, M., Narumiya, S., Fukumoto, M., Overexpression of the RhoC gene correlates with progression of ductal adenocarcinoma of the pancreas (1998) Br J Cancer, 77, pp. 147-155; Takai, Y., Sasaki, T., Matozaki, T., Small GTP-binding proteins (2001) Physiol Rev, 81, pp. 153-208; Tapon, N., Nagata, K., Lamarche, N., Hall, A., A new Rac target POSH is an SH3-containing scaffold protein involved in the JNK and NF-3B signalling pathways (1998) EMBO J, 17, pp. 1395-1404; Van Golen, K.L., Wu, Z.F., Qiao, X.T., Bao, L.W., Merajver, S.D., RhoC GTPase, a novel transforming oncogene for human mammary epithelial cells that partially recapitulates the inflammatory breast cancer phenotype (2000) Cancer Res, 60, pp. 5832-5838; Wu, C.-W., Hsieh, M.-C., Lo, S.-S., Lui, W.-Y., P'eng, F.-K., Results of curative gastrectomy for carcinoma of the distal third of the stomach (1996) J Am Coll Surg, 183, pp. 201-207; Wu, C.-W., Hsieh, M.-C., Lo, S.-S., Tsay, S.-H., Li, A.F., Lui, W.-Y., P'eng, F.-K., Prognostic indicators for survival after curative resection for patients with carcinoma of the stomach (1997) Dig Dis Sci, 42, pp. 1265-1269; Wu, C.-W., Hsieh, M.-C., Lo, S.-S., Tsay, S.-H., Lui, W.-Y., P'eng, F.-K., Relation of number of positive lymph nodes to the prognosis of patients with primary gastric adenocarcinoma (1996) Gut, 38, pp. 525-527; Zhou, J., Zhao, L.-Q., Xiong, M.-M., Wang, X.-Q., Yang, G.-R., Qiu, Z.-L., Wu, M.-S., Liu, Z.-H., Gene expression profiles at different stages of human esophageal squamous cell carcinoma (2003) World J Gastroenterol, 9, pp. 9-15",
year = "2004",
doi = "10.1159/000079679",
language = "English",
volume = "11",
pages = "661--670",
journal = "Journal of Biomedical Science",
issn = "1021-7770",
publisher = "BioMed Central",
number = "5",

}

TY - JOUR

T1 - Overexpression of Rho effector rhotekin confers increased survival in gastric adenocarcinoma

AU - Liu, Ching-Ann

AU - Wang, Mei-Jung

AU - Chi, Chin-Wen

AU - Wu, Chew-Wun

AU - Chen, Jeou-Yuan

N1 - 被引用次數:14 Export Date: 28 March 2016 CODEN: JBCIE 通訊地址: Chen, J.-Y.; Institute of Biomedical Sciences, Academia Sinica, 128 Section 2 Yen-Chiu-Yuan Road, Taipei 11529, Taiwan; 電子郵件: bmchen@ibms.sinica.edu.tw 化學物質/CAS: butyric acid, 107-92-6, 156-54-7, 461-55-2; DNA Primers; Intracellular Signaling Peptides and Proteins; NF-kappa B; RTKN protein, human 參考文獻: Bishop, A.L., Hall, A., Rho GTPases and their effector proteins (2000) Biochem J, 348, pp. 241-255; Brizzard, B.L., Chubet, R.G., Vizard, D.L., Immunoaffinity purification of FLAG epitope-tagged bacterial alkaline phosphatase using a novel monoclonal antibody and peptide elution (1994) Biotechniques, 16, pp. 730-735; Cammarano, M.S., Minden, A., Dbl and the Rho GTPases activate NF B by IBB kinase (IKK)-dependent and IKK-independent pathways (2001) J Biol Chem, 276, pp. 25876-25882; Chen, J.-Y., Funk, W.D., Wright, W.E., Shay, J.W., Minna, J.D., Heterogeneity of transcriptional activity of mutant p53 proteins and p53 DNA target sequences (1993) Oncogene, 8, pp. 2159-2166; Chuang, S.-E., Yeh, P.-Y., Lu, Y.-S., Lai, G.-M., Liao, C.-M., Gao, M., Cheng, A.-L., Basal levels and patterns of anticancer drug-induced activation of nuclear factor-kB (NF-CB), and its attenuation by tamoxifen, dexamethasone, and curcumin in carcinoma cells (2002) Biochem Pharmacol, 63, pp. 1709-1716; Clark, E.A., Golub, T.R., Lander, E.S., Hynes, R.O., Genomic analysis of metastasis reveals an essential role for RhoC (2000) Nature, 406, pp. 532-535; Del Peso, L., Hernandez-Alcoceba, R., Embade, N., Carnero, A., Esleve, P., Paje, C., Lacal, J.C., Rho proteins induce metastatic properties in vivo (1997) Oncogene, 15, pp. 3047-3057; Donovan, S., Shannon, K.M., Bollag, G., GTPase activating proteins: Critical regulators of intracellular signaling (2002) Biochim Biophys Acta, 1602, pp. 23-45; Engers, R., Zwaka, T.P., Gohr, L., Weber, A., Gerharz, C.D., Gabbert, H.E., Tiam1 mutations in human renal-cell carcinomas (2000) Int J Cancer, 88, pp. 369-376; Fritz, G., Brachetti, C., Schmidt, M., Kaina, B., Rho GTPases in human breast tumours: Expression and mutation analyses and correlation with clinical parameters (2002) Br J Cancer, 87, pp. 635-644; Fritz, G., Just, I., Kaina, B., Rho GTPases are over-expressed in human tumors (1999) Int J Cancer, 81, pp. 682-687; Fu, Q., Yu, L., Liu, Q., Zhang, J., Zhang, H., Zhao, S., Molecular cloning, expression characterization, and mapping of a novel putative inhibitor of Rho GTPase activity, RTKN, to D2S145-D2S286 (2000) Genomics, 66, pp. 328-332; Hall, A., Nobes, C.D., Rho GTPases: Molecular switches that control the organization and dynamics of the actin cytoskeleton (2000) Philos Trans R Soc Lond B Biol Sci, 355, pp. 965-970; Ikeda, H., Nagashima, K., Yanase, M., Tomiya, T., Arai, M., Inoue, Y., Tejima, K., Fujiwara, K., Involvement of Rho/Rho kinase pathway in regulation of apoptosis in rat hepatic stellate cells (2003) Am J Physiol Gastrointest Liver Physiol, 285, pp. G880-G886; Kamai, T., Arai, S., Sumi, T., Tsujii, M., Honda, T., Yamanishi, T., Yoshida, K.I., The rho/rho-kinase pathway is involved in the progression of testicular germ cell tumor (2003) BJU Int, 89, pp. 449-453; Kanai, M., Konda, Y., Nakajima, T., Izumi, Y., Takeuchi, T., Chiba, T., TGF-alpha inhibits apoptosis of murine gastric pit cells through an NF-κB-dependent pathway (2001) Gastroenterology, 121, pp. 56-67; Kaneko, K., Satoh, K., Masamune, A., Satoh, A., Shimosegawa, T., Expression of ROCK-1 in human pancreatic cancer: Its down-regulation by morpholino oligo antisense can reduce the migration of pancreatic cancer cells in vitro (2002) Pancreas, 24, pp. 251-257; Karin, M., Cao, Y., Greten, F.R., Li, Z.W., NF-kappaB in cancer: From innocent bystander to major culprit (2002) Nat Rev Cancer, 2, pp. 301-310; Kim, N.S., Lee, G.M., Inhibition of sodium butyrate-induced apoptosis in recombinant Chinese hamster ovary cells by constitutively expressing antisense RNA of caspase-3 (2002) Biotechnol Bioeng, 78, pp. 217-228; Kourlas, P.J., Strout, M.P., Becknell, B., Veronese, M.L., Croce, C.M., Theil, K.S., Krahe, R., Caligiuri, M.A., Identification of a gene at 11q23 encoding a guanine nucleotide exchange factor: Evidence for its fusion with MLL in acute myeloid leukemia (2000) Proc Natl Acad Sci USA, 97, pp. 2145-2150; Lai, J.-M., Lu, C.-Y., Yen-Yang, H.-F., Chang, Z.-F., Lysophosphatidic acid promotes phorbol-ester-induced apoptosis in TF-1 cells by interfering with adhesion (2001) Biochem J, 359, pp. 227-233; Leung, S.Y., Chen, X., Chu, K.M., Yuen, S.T., Mathy, J., Ji, J., Chan, A.S.Y., Brown, P.O., Phospholipase A2 group IIA expression in gastric adenocarcinoma is associated with prolonged survival and less frequent metastasis (2002) Proc Natl Acad Sci USA, 99, pp. 16203-16208; Matz, M., Usman, N., Shagin, D., Bogdanova, E., Lukyanov, S., Ordered differential display: A simple method for systematic comparison of gene expression profiles (1997) Nucleic Acids Res, 25, pp. 2541-2542; Metzger, E., Muller, J.M., Ferrari, S., Buettner, R., Schule, R., A novel inducible transactivation domain in the androgen receptor: Implications for PRK in prostate cancer (2003) EMBO J, 22, pp. 270-280; Olofsson, B., Rho guanine dissociation inhibitors: Pivotal molecules in cellular signaling (1999) Cell Signal, 11, pp. 545-554; Perona, R., Montaner, S., Saniger, L., Sanchez-Perez, I., Bravo, R., Lacal, J.C., Activation of the nuclear factor-2B by Rho, CDC42, and Rac-1 proteins (1997) Genes Dev, 11, pp. 463-475; Reid, T., Furuyashiki, T., Ishizaki, T., Watanabe, G., Watanabe, N., Fujisawa, K., Morii, N., Narumiya, S., Rhotekin, a new putative target for Rho bearing homology to a serine/threonine kinase, PKN, and rhophilin in the rho-binding domain (1996) J Biol Chem, 271, pp. 13556-13560; Reynaud, C., Fabre, S., Jalinot, P., The PDZ protein TIP-1 interacts with the Rho effector rhotekin and is involved in Rho signaling to the serum response element (2000) J Biol Chem, 275, pp. 33962-33968; Schmidt, A., Hall, A., Guanine nucleotide exchange factors for Rho GTPases: Turning on the switch (2002) Genes Dev, 16, pp. 1587-1609; Schnelzer, A., Prechtel, D., Knaus, U., Dehne, K., Gerhard, M., Graeff, H., Harbeck, N., Lengyel, E., Rac1 in human breast cancer: Overexpression, mutation analysis, and characterization of a new isoform, Rac1b (2000) Oncogene, 19, pp. 3013-3020; Srivastava, S.K., Wheelock, R.H., Aaronson, S.A., Eva, A., Identification of the protein encoded by the human diffuse B-cell lymphoma (dbl) oncogene (1986) Proc Natl Acad Sci USA, 83, pp. 8868-8872; Suwa, H., Ohshio, G., Imamura, T., Watanabe, G., Arii, S., Imamura, M., Narumiya, S., Fukumoto, M., Overexpression of the RhoC gene correlates with progression of ductal adenocarcinoma of the pancreas (1998) Br J Cancer, 77, pp. 147-155; Takai, Y., Sasaki, T., Matozaki, T., Small GTP-binding proteins (2001) Physiol Rev, 81, pp. 153-208; Tapon, N., Nagata, K., Lamarche, N., Hall, A., A new Rac target POSH is an SH3-containing scaffold protein involved in the JNK and NF-3B signalling pathways (1998) EMBO J, 17, pp. 1395-1404; Van Golen, K.L., Wu, Z.F., Qiao, X.T., Bao, L.W., Merajver, S.D., RhoC GTPase, a novel transforming oncogene for human mammary epithelial cells that partially recapitulates the inflammatory breast cancer phenotype (2000) Cancer Res, 60, pp. 5832-5838; Wu, C.-W., Hsieh, M.-C., Lo, S.-S., Lui, W.-Y., P'eng, F.-K., Results of curative gastrectomy for carcinoma of the distal third of the stomach (1996) J Am Coll Surg, 183, pp. 201-207; Wu, C.-W., Hsieh, M.-C., Lo, S.-S., Tsay, S.-H., Li, A.F., Lui, W.-Y., P'eng, F.-K., Prognostic indicators for survival after curative resection for patients with carcinoma of the stomach (1997) Dig Dis Sci, 42, pp. 1265-1269; Wu, C.-W., Hsieh, M.-C., Lo, S.-S., Tsay, S.-H., Lui, W.-Y., P'eng, F.-K., Relation of number of positive lymph nodes to the prognosis of patients with primary gastric adenocarcinoma (1996) Gut, 38, pp. 525-527; Zhou, J., Zhao, L.-Q., Xiong, M.-M., Wang, X.-Q., Yang, G.-R., Qiu, Z.-L., Wu, M.-S., Liu, Z.-H., Gene expression profiles at different stages of human esophageal squamous cell carcinoma (2003) World J Gastroenterol, 9, pp. 9-15

PY - 2004

Y1 - 2004

N2 - Like many epithelial-derived cancers, gastric cancer (GC) results from a multistep tumorigenic process. However, the detailed mechanisms involved in GC formation are poorly characterized. Using an ordered differential display method, we have identified rhotekin (RTKN), the gene coding for the Rho effector, RTKN, as one of the genes differentially expressed in human GC. Northern analysis using human multiple tissue blots showed that RTKN is predominantly expressed in the kidney and spinal cord, and, to a lesser degree, in the thyroid, tongue, liver, brain, prostate, trachea, and stomach. RT-PCR analysis confirmed that RTKN was overexpressed in most (5/7; 71%) GC examined. By analyzing the Stanford Microarray Database for the expression profiles of gastric tissues, we also found a progressional increase in RTKN expression in nonneoplastic mucosa, GC, and then lymph node metastases (p <0.005 by Jonckheere-Terpstra test), suggesting that RTKN expression correlates with GC progression. The role of RTKN in the pathogenic development of GC was investigated by transfection and expression of RTKN in AGS gastric cells, which express endogenous RTKN at a low basal level. Flow-cytometric analysis showed that RTKN-transfected AGS cells were significantly more resistant than vector-transfected cells to apoptosis upon treatment with sodium butyrate. To explore the mechanisms underlying RTKN-mediated cell survival, a reporter assay was performed. Since the NF-κB activation is known to promote cell survival and Rho GTPase may lead to NF-κB activation, we transfected AGS cells with the RTKN expression vector along with a pNF-κB-Luc reporter plasmid. Our results showed that overexpression of RTKN induced robust activation of NF-κB, and RTKN-mediated NF-κB activation was suppressed significantly by C3 transferase, an inhibitor of the small GTPase Rho. We conclude that Rho/RTKN-mediated NF-κB activation leading to cell survival may play a key role in gastric tumorigenesis. This study provides original documentation for the overrepresentation of the Rho GTPase effector rhotekin in human cancer and its links to cancer formation. Copyright © 2004 National Science Council, ROC and S. Karger AG, Basel.

AB - Like many epithelial-derived cancers, gastric cancer (GC) results from a multistep tumorigenic process. However, the detailed mechanisms involved in GC formation are poorly characterized. Using an ordered differential display method, we have identified rhotekin (RTKN), the gene coding for the Rho effector, RTKN, as one of the genes differentially expressed in human GC. Northern analysis using human multiple tissue blots showed that RTKN is predominantly expressed in the kidney and spinal cord, and, to a lesser degree, in the thyroid, tongue, liver, brain, prostate, trachea, and stomach. RT-PCR analysis confirmed that RTKN was overexpressed in most (5/7; 71%) GC examined. By analyzing the Stanford Microarray Database for the expression profiles of gastric tissues, we also found a progressional increase in RTKN expression in nonneoplastic mucosa, GC, and then lymph node metastases (p <0.005 by Jonckheere-Terpstra test), suggesting that RTKN expression correlates with GC progression. The role of RTKN in the pathogenic development of GC was investigated by transfection and expression of RTKN in AGS gastric cells, which express endogenous RTKN at a low basal level. Flow-cytometric analysis showed that RTKN-transfected AGS cells were significantly more resistant than vector-transfected cells to apoptosis upon treatment with sodium butyrate. To explore the mechanisms underlying RTKN-mediated cell survival, a reporter assay was performed. Since the NF-κB activation is known to promote cell survival and Rho GTPase may lead to NF-κB activation, we transfected AGS cells with the RTKN expression vector along with a pNF-κB-Luc reporter plasmid. Our results showed that overexpression of RTKN induced robust activation of NF-κB, and RTKN-mediated NF-κB activation was suppressed significantly by C3 transferase, an inhibitor of the small GTPase Rho. We conclude that Rho/RTKN-mediated NF-κB activation leading to cell survival may play a key role in gastric tumorigenesis. This study provides original documentation for the overrepresentation of the Rho GTPase effector rhotekin in human cancer and its links to cancer formation. Copyright © 2004 National Science Council, ROC and S. Karger AG, Basel.

KW - Antiapoptosis

KW - Effectors

KW - Gastric cancer

KW - Nuclear factor-κB

KW - Rho GTPases

KW - butyric acid

KW - immunoglobulin enhancer binding protein

KW - regulator protein

KW - Rho guanine nucleotide binding protein

KW - rhotekin

KW - unclassified drug

KW - apoptosis

KW - article

KW - brain

KW - cancer growth

KW - carcinogenesis

KW - cell survival

KW - controlled study

KW - correlation analysis

KW - data base

KW - differential display

KW - female

KW - flow cytometry

KW - gene expression profiling

KW - gene expression regulation

KW - gene identification

KW - gene overexpression

KW - genetic transfection

KW - human

KW - human cell

KW - human tissue

KW - kidney

KW - liver

KW - lymph node metastasis

KW - male

KW - Northern blotting

KW - plasmid

KW - priority journal

KW - prostate

KW - protein function

KW - reverse transcription polymerase chain reaction

KW - spinal cord

KW - statistical significance

KW - stomach

KW - stomach adenocarcinoma

KW - thyroid gland

KW - tissue distribution

KW - tongue

KW - trachea

KW - Adenocarcinoma

KW - Base Sequence

KW - Cell Survival

KW - DNA Primers

KW - Flow Cytometry

KW - Gene Expression Profiling

KW - Humans

KW - Intracellular Signaling Peptides and Proteins

KW - NF-kappa B

KW - Organ Specificity

KW - Polymerase Chain Reaction

KW - Restriction Mapping

KW - Reverse Transcriptase Polymerase Chain Reaction

KW - Stomach Neoplasms

KW - vectors

U2 - 10.1159/000079679

DO - 10.1159/000079679

M3 - Article

VL - 11

SP - 661

EP - 670

JO - Journal of Biomedical Science

JF - Journal of Biomedical Science

SN - 1021-7770

IS - 5

ER -