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ABSTRACT: By using genome-wide methylation screening, the authors identified ring finger protein 180 (RNF180) as preferentially methylated in cancer. This study was undertaken to clarify its structure and functional role in gastric cancer.
The transcription start site and core functional promoter region of RNF180 were revealed by 5' rapid amplification of cDNA ends and luciferase activity assays. Promoter methylation was detected by combined bisulfite restriction analysis and bisulfite genomic sequencing. Cell growth was detected by colony formation assay, apoptosis by annexin V assay, and RNF180 target genes by cDNA microarray.
The authors revealed the transcription start site of RNF180 gene and identified the functional core promoter region (-202/+372) in the CpG island, which could be silenced by in vitro methylation assay. RNF180 was silenced in 6 of 7 gastric cancer cell lines and significantly down-regulated in primary gastric cancers compared with adjacent normal tissues (P = .001). Loss of gene expression was associated with promoter methylation. Re-expression of RNF180 suppressed cell growth (P < .001) and induced apoptosis (P < .05), which were mediated by up-regulating the antiproliferation regulators MTSS1 and CDKN2A and the proapoptotic mediator TIMP3. Promoter methylation of RNF180 was detected in 76% (150 of 198) of primary gastric cancers and 55% (11 of 20) of intestinal metaplasia, but in none of 23 normal gastric tissues. Methylated RNF180 DNA was detected in the plasma of 56% of gastric cancer patients, but not in healthy controls (P = .003). Patients with low or loss of RNF180 expression had significantly poorer overall survival.
RNF180 is a novel potential tumor suppressor in gastric carcinogenesis and has potential clinical utility as a biomarker for gastric cancer patients.
Cancer 06/2011; 118(4):947-59. · 4.77 Impact Factor
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ABSTRACT: Nuclear factor-kappa B inhibitor alpha (IκBα) polymorphisms were found to be associated with inflammatory diseases. However, the association between IκBα polymorphisms with gastric cancer is still unknown. We aim to investigate the association between IκBα polymorphisms and gastric cancer risk in a large population-based case-control study among southern Chinese.
A population-based case-control study was conducted between 1999 and 2006 in Guangdong Province, China. A total of 1010 gastric cancer patients and 1500 healthy controls were enrolled in this study. IκBα polymorphisms were identified by sequencing of IκBα gene ranging from the 2kb promoter region to the 3.5kb genomic region. Polymorphisms in IκBα were analyzed by TaqMan SNP genotyping assay.
rs17103265 deletion homozygote (-/-) had significantly increased gastric cancer risk (OR=2.11, 95% CI=1.17-3.83, P=0.01), compared with rs17103265 T homozygote (TT). rs17103265 (-/-) genotype was significantly associated with increased risk of intestinal-type gastric cancer with (OR=2.21, 95% CI=1.19-4.08, P=0.01), but not with the diffuse or mix type of gastric cancer. rs17103265 (-/-) was associated with poorly differentiated gastric cancer (OR=2.05, 95% CI=1.07-3.94, P=0.03), but not with moderately or well differentiated gastric cancer. A significant decrease in luciferase activity was observed in rs17103265 deletion allele as compared with the vector containing the rs17103265 T allele (P<0.0001). rs17103265 polymorphism was not associated with the prognosis of gastric cancer patients.
IκBα rs17103265 deletion homozygote is a novel genetic risk factor for gastric carcinogenesis, especially for the development of certain subtypes of gastric cancer in southern Chinese population.
Life sciences 03/2011; 88(17-18):792-7. · 2.56 Impact Factor
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Wei Kang,
Joanna H M Tong,
Anthony W H Chan,
Tin-Lap Lee,
Raymond W M Lung,
Patrick P S Leung,
Ken K Y So, Kaichun Wu,
Daiming Fan,
Jun Yu,
Joseph J Y Sung,
Ka-Fai To
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ABSTRACT: Yes-associated protein 1 (YAP1) is a multifunctional protein that can interact with different transcription factors to activate gene expression. The role of YAP1 in tumorigenesis is unclear. We aimed to investigate the functional role of YAP1 in tumorigenesis of gastric cancer.
YAP1 expression in gastric adenocarcinoma was evaluated. The biological function was determined by proliferation assay, colony formation, cell invasion, and flow cytometric analysis through knocking down or ectopic expressing YAP1 in gastric cancer cell lines coupled with in vivo study. The possible downstream effectors of YAP1 were investigated by expression microarray.
YAP1 protein expression was upregulated in gastric cancer. Nuclear accumulation of YAP1 was associated with poor disease-specific survival (P = 0.021), especially in patients with early-stage diseases (P < 0.001). Knockdown YAP1 resulted in a significant reduction in proliferation, anchorage-dependent colony formation, cell invasion, and cell motility. Ectopic YAP1 expression promoted anchorage-independent colony formation, induced a more invasive phenotype, and accelerated cell growth both in vitro and in vivo. Microarray analysis highlighted the alteration of MAPK (mitogen-activated protein kinase) pathway by YAP1. We confirmed a constitutive activation of RAF/MEK/ERK (extracellular signal-regulated kinase) in YAP1-expressing MKN45 cells and further showed that YAP1 enhanced serum/epidermal growth factor-induced c-Fos expression in gastric cancer cells.
Our findings supported that YAP1 exhibits oncogenic property in gastric cancer. We provided the first evidence that YAP1 exerted the oncogenic function by enhancing the capacity to activate the early-response gene pathway. YAP1 could be a prognostic biomarker and potential therapeutic target for gastric cancer.
Clinical Cancer Research 02/2011; 17(8):2130-9. · 7.74 Impact Factor
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ABSTRACT: Colon carcinogenesis represents a stepwise progression from benign polyps to invasive adenocarcinomas and distant metastasis. It is believed that these pathologic changes are contributed by aberrant activation or inactivation of protein-coding proto-oncogenes and tumor suppressor genes. However, recent discoveries in microRNA (miRNA) research have reshaped our understanding of the role of non-protein-coding genes in carcinogenesis. In this regard, a remarkable number of miRNAs exhibit differential expression in colon cancer tissues. These miRNAs alter cell proliferation, apoptosis and metastasis through their interactions with intracellular signaling networks. From a clinical perspective, polymorphisms within miRNA-binding sites are associated with the risk for colon cancer, whereas miRNAs isolated from feces or blood may serve as biomarkers for early diagnosis. Altered expression of miRNA or polymorphisms in miRNA-related genes have also been shown to correlate with patient survival or treatment outcome. With further insights into miRNA dysregulation in colon cancer and the advancement of RNA delivery technology, it is anticipated that novel miRNA-based therapeutics will emerge.
Carcinogenesis 11/2010; 32(3):247-53. · 5.70 Impact Factor
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ABSTRACT: Human cathelicidin LL-37, a host defense peptide derived from leukocytes and epithelial cells, plays a crucial role in innate and adaptive immunity. Not only does LL-37 eliminate pathogenic microbes directly but also modulates host immune responses. Emerging evidence from tumor biology studies indicates that LL-37 plays a prominent and complex role in carcinogenesis. Although overexpression of LL-37 has been implicated in the development or progression of many human malignancies, including breast, ovarian and lung cancers, LL-37 suppresses tumorigenesis in gastric cancer. These data are beginning to unveil the intricate and contradictory functions of LL-37. The reasons for the tissue-specific function of LL-37 in carcinogenesis remain to be elucidated. Here, we review the relationship between LL-37, its fragments and cancer progression as well as discuss the potential therapeutic implications of targeting this peptide.
International Journal of Cancer 10/2010; 127(8):1741-7. · 5.44 Impact Factor
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ABSTRACT: The pathogenesis of gastric cancer is complex and related to multiple factors. Dysregulation of intracellular signaling pathways represents a common pathogenic mechanism and may be amenable to drug targeting. Multiple well-established oncogenic pathways, such as those mediated by cell cycle regulators, nuclear factor-kappaB, cyclooxygenase-2 and epidermal growth factor receptor are implicated in gastric carcinogenesis. Emerging evidence also underscores the importance of signaling pathways involved in the developmental process, including transforming growth factor-beta/bone morphogenetic protein signaling, Wnt/beta-catenin signaling, Hedgehog signaling and Notch signaling. Understanding their biological significance will provide a rational basis for drug development. Their relative importance and cross-talk in gastric carcinogenesis, however, are still not completely understood and warrant further investigation.
Cancer letters 09/2010; 295(2):144-53. · 4.86 Impact Factor
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ABSTRACT: The ubiquitin-proteasome system is a major pathway for protein degradation. Targeting this pathway using proteasome inhibitors represents a novel approach for the treatment of cancer. Proteasome inhibitors lower cell proliferation and induce apoptosis in solid and hematologic malignancies through multiple mechanisms, including stabilization of cell cycle regulators and pro-apoptotic factors, stimulation of bone morphogenetic protein signaling, inhibition of protein translation, and sensitization to ligand-induced apoptosis. In this connection, proteasome inhibition activates macroautophagy, a compensatory protein degradation system, as well as other pro-survival signaling pathways. Inhibition of these auto-protective responses sensitizes cancer cells to the anti-proliferative effects of proteasome inhibitors.
Cancer letters 07/2010; 293(1):15-22. · 4.86 Impact Factor
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ABSTRACT: Human cathelicidin LL-37, a host defense peptide derived from leukocytes and epithelial cells, plays a crucial role in innate and adaptive immunity. Not only does LL-37 eliminate pathogenic microbes directly but also modulates host immune responses. Emerging evidence from tumor biology studies indicates that LL-37 plays a prominent and complex role in carcinogenesis. Although overexpression of LL-37 has been implicated in the development or progression of many human malignancies, including breast, ovarian and lung cancers, LL-37 suppresses tumorigenesis in gastric cancer. These data are beginning to unveil the intricate and contradictory functions of LL-37. The reasons for the tissue-specific function of LL-37 in carcinogenesis remain to be elucidated. Here, we review the relationship between LL-37, its fragments and cancer progression as well as discuss the potential therapeutic implications of targeting this peptide.
International Journal of Cancer 06/2010; 127(8):1741 - 1747. · 5.44 Impact Factor
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ABSTRACT: Macroautophagy and the ubiquitin-proteasome system are two complementary pathways for protein degradation. The former degrades long-lived proteins and damaged organelles while the later degrades short-lived proteins. Recent findings indicate that suppression of the ubiquitin-proteasome system by proteasome inhibitors induces macroautophagy through multiple pathways, including (1) accumulation of ubiquitinated proteins and activation of HDAC6; (2) activation of the IRE1-JNK pathway; (3) proteasomal stabilization of ATF4; (4) inhibition of mTOR complex 1 signaling; (5) reduced proteasomal degradation of LC3. Induction of macroautophagy attenuates the antitumor effect of proteasome inhibitors in various types of cancer. These findings suggest that inhibition of macroautophagy may represent a novel strategy to enhance cellular sensitivity to proteasome inhibition.
Drug resistance updates: reviews and commentaries in antimicrobial and anticancer chemotherapy 06/2010; 13(3):87-92. · 12.58 Impact Factor
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William Ka Kei Wu,
Chi Hin Cho,
Chung Wa Lee,
Ya Chun Wu,
Le Yu,
Zhi Jie Li,
Clover Ching Man Wong,
Hai Tao Li,
Lin Zhang,
Shun Xiang Ren,
Chun Tao Che, Kaichun Wu,
Daiming Fan,
Jun Yu,
Joseph Jao Yiu Sung
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ABSTRACT: The ubiquitin-proteasome system and macroautophagy are two complementary pathways for protein degradation. Emerging evidence suggests that proteasome inhibition might be a promising approach for the treatment of cancer. In this study, we show that proteasome inhibitor MG-132 suppressed gastric cancer cell proliferation and induced macroautophagy. The induction of macroautophagy was evidenced by the formation of LC3(+) autophagosomes and the accumulation of acidic vesicular organelles and autolysosomes and was accompanied by the suppression of mammalian target of rapamycin complex 1 activity. Abolition of macroautophagy by knockdown of Class III phosphatidylinositol-3 kinase Vps34 or ATG5/7 sensitized gastric cancer cells to the antiproliferative effect of MG-132 by promoting G(2)/M cell cycle arrest. In addition, MG-132 increased ERK phosphorylation whose inhibition by MEK inhibitor significantly enhanced the antiproliferative effect of proteasome inhibition. To conclude, this study demonstrates that macroautophagy and ERK phosphorylation serve as protective mechanisms to counteract the antiproliferative effect of proteasome inhibition. This discovery may have implications for the application of proteasome-directed therapy for the treatment of cancer.
Autophagy 02/2010; 6(2):228-38. · 7.45 Impact Factor
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ABSTRACT: Nuclear factor of kappa B inhibitor alpha (I kappaB alpha) protein is implicated in regulating a variety of cellular process from inflammation to tumorigenesis. The objective of this study was to investigate the susceptibility of rs2233408 T/C genotype in the promoter region of I kappaB alpha to gastric cancer and the association of this polymorphism with clinicopathologic variables in gastric cancer patients.
A population-based case-control study was conducted between 1999 and 2006 in Guangdong Province, China. A total of 564 gastric cancer patients and 566 healthy controls were enrolled in this study. rs2233408 genotypes in I kappaB alpha were analyzed by TaqMan SNP genotyping assay.
Both rs2233408 T homozygote (TT) and T heterozygotes (TC and TT) had significantly reduced gastric cancer risk (TT: OR = 0.250, 95% CI = 0.069-0.909, P = 0.035; TC and TT: OR = 0.721, 95% CI = 0.530-0.981, P = 0.037), compared with rs2233408 C homozygote (CC). rs2233408 T heterozygotes were significantly associated with reduced risk of intestinal-type gastric cancer with ORs of 0.648 (95% CI = 0.459-0.916, P = 0.014), but not with the diffuse or mix type of gastric cancer. The association between rs2233408 T heterozygotes and gastric cancer appeared more apparent in the older patients (age>40) (OR = 0.674, 95% CI = 0.484-0.939, P = 0.02). rs2233408 T heterozygotes was associated with non-cardiac gastric cancer (OR = 0.594, 95% CI = 0.411-0.859, P = 0.006), but not with cardiac gastric cancer. However, rs2233408 polymorphism was not associated with the prognosis of gastric cancer patients.
I kappaB alpha rs2233408 T heterozygotes were associated with reduced risk of gastric cancer, especially for the development of certain subtypes of gastric cancer in Chinese population.
BMC Gastroenterology 01/2010; 10:15. · 2.42 Impact Factor
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ABSTRACT: Abstract
Background
Nuclear factor of kappa B inhibitor alpha (IκBα) protein is implicated in regulating a variety of cellular process from inflammation to tumorigenesis. The objective of this study was to investigate the susceptibility of rs2233408 T/C genotype in the promoter region of IκBα to gastric cancer and the association of this polymorphism with clinicopathologic variables in gastric cancer patients.
Methods
A population-based case-control study was conducted between 1999 and 2006 in Guangdong Province, China. A total of 564 gastric cancer patients and 566 healthy controls were enrolled in this study. rs2233408 genotypes in IκBα were analyzed by TaqMan SNP genotyping assay.
Results
Both rs2233408 T homozygote (TT) and T heterozygotes (TC and TT) had significantly reduced gastric cancer risk (TT: OR = 0.250, 95% CI = 0.069-0.909, P = 0.035; TC and TT: OR = 0.721, 95% CI = 0.530-0.981, P = 0.037), compared with rs2233408 C homozygote (CC). rs2233408 T heterozygotes were significantly associated with reduced risk of intestinal-type gastric cancer with ORs of 0.648 (95% CI = 0.459-0.916, P = 0.014), but not with the diffuse or mix type of gastric cancer. The association between rs2233408 T heterozygotes and gastric cancer appeared more apparent in the older patients (age>40) (OR = 0.674, 95% CI = 0.484-0.939, P = 0.02). rs2233408 T heterozygotes was associated with non-cardiac gastric cancer (OR = 0.594, 95% CI = 0.411-0.859, P = 0.006), but not with cardiac gastric cancer. However, rs2233408 polymorphism was not associated with the prognosis of gastric cancer patients.
Conclusions
IκBα rs2233408 T heterozygotes were associated with reduced risk of gastric cancer, especially for the development of certain subtypes of gastric cancer in Chinese population.
BMC Gastroenterology. 01/2010;
