New advances in targeted gastric cancer treatment

Lazăr, Daniela; Tăban, Sorina; Cornianu, Mărioara; A, Faur; Goldiş, Adrian

doi:10.3748/wjg.v22.i30.6776

Cited by 81 publications

(66 citation statements)

References 189 publications

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“…However, the prognostic conditions of advanced cases remain undesirable. [2][3][4] It has been progressively realized that altered epigenetics, particularly changed DNA methylations are responsible for various kinds of carcinomas Iacobuzio-Donahue. [5][6][7] The process of inactivating anti-oncogenes, which participates in regulating cell cycles, DNA reparation as well as apoptosis is related to hypermethylated regulatory elements, which prevent transcriptional factors from binding to the corresponding recognition elements.…”

Section: Introductionmentioning

confidence: 99%

DNA hypomethylation promotes invasion and metastasis of gastric cancer cells by regulating the binding of SP1 to the CDCA3 promoter

Hua

Zhang

et al. 2019

J of Cellular Biochemistry

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Background Cell division cycle associated protein‐3 (CDCA3) has been reported frequently upregulated in various cancers. It has been progressively realized that changed DNA methylations occur in diverse carcinomas. However, the concrete involvement of CDCA3 and DNA methylation in gastric cancer (GC) still needs to be further elucidated. Methods In this study, quantitative reverse‐transcription polymerase chain reaction (PCR) was utilized to determine the relative expressions of CDCA3 in GC and normal tissue samples. The methylation condition of CDCA3 was determined by bisulfite‐sequencing PCR (BSP) and methylation‐specific PCR (MSP). A chromatin immunoprecipitation (ChIP) assay and luciferase activity assay was used for the interaction between transcription factors and promoters and binding site determination, respectively. The effects of knockdown or overexpression of specificity protein 1 (SP1) or CDCA3 on GC cells in vitro were further assessed via wound healing assay, colony formation assay, and matrigel invasion assay. Results In comparison to paired normal tissues, CDCA3 expressions were significantly increased in the GC tissues. The CDCA3 expression was regulated by DNA methylation, with the CpG island hypomethylation responsible for CDCA3 upregulation of GC. ChIP assays verified that the activity of SP1 binding to the CDCA3 promoter was dramatically increased. When the CDCA3 expression was downregulated in MKN45 cells by knockdown SP1, the proliferation ability, healing ability, and invasive ability were significantly suppressed. Conclusion The process by which SP1 bound to the nearest promoter region was expedited in GC cells, by which DNA was hypomethylated and CDCA3 expression was promoted. The effect on cell proliferation and invasion by CDCA3 was under the regulation of SP1 and also affected by hypomethylation of DNA.

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Section: Introductionmentioning

confidence: 99%

DNA hypomethylation promotes invasion and metastasis of gastric cancer cells by regulating the binding of SP1 to the CDCA3 promoter

Hua

Zhang

et al. 2019

J of Cellular Biochemistry

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“…Although significant progress has been made in its diagnosis as well as in surgical combined adjuvant approaches, the outcomes of GC patients have only modestly improved [1]. In recent decades, considerable research has indicated that several signaling pathways are involved in gastric carcinogenesis and GC progression.…”

Section: Introductionmentioning

confidence: 99%

Downregulated PITX1 Modulated by MiR-19a-3p Promotes Cell Malignancy and Predicts a Poor Prognosis of Gastric Cancer by Affecting Transcriptionally Activated PDCD5

Qiao

Gong

Song

et al. 2018

Cell Physiol Biochem

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Background/Aims: PITX1 has been identified as a potential tumor-suppressor gene in several malignant tumors. The molecular mechanism underlying PITX1, particularly its function as a transcription factor regulating gene expression during tumorigenesis, is still poorly understood. Methods: The expression level and location of PITX1 were determined by quantitative reverse transcription PCR (qRT-PCR) and immunohistochemical staining in gastric cancer (GC). The effect of PITX1 on the GC cell proliferation and tumorigenesis was analyzed in vitro and in vivo. To explore how PITX1 suppresses cell proliferation, we used PITX1-ChIP-sequencing to measure genome-wide binding sites of PITX1 and assessed global function associations based on its putative target genes. ChIP-PCR, electrophoretic mobility shift assay, and promoter reporter assays examined whether PITX1 bound to PDCD5 and regulated its expression. The function of PDCD5 in GC cell apoptosis was further examined in vitro and in vivo. The relationship between the PITX1 protein level and GC patient prognosis was evaluated by the Kaplan-Meier estimator. Meanwhile, the expression level of miR-19a-3p, which is related to PITX1, was also detected by luciferase reporter assay, qRT-PCR, and western blotting. Results: The expression level of PITX1 was decreased in GC tissues and cell lines. Elevated PITX1 expression significantly suppressed the cell proliferation of GC cells and tumorigenesis in vitro and in vivo. PITX1 knockdown blocked its inhibition of GC cell proliferation. PITX1 bound to whole genomewide sites, with these targets enriched on genes with functions mainly related to cell growth and apoptosis. PITX1 bound to PDCD5, an apoptosis-related gene, during tumorigenesis, and cis-regulated PDCD5 expression. Increased PDCD5 expression in GC cells not only induced GC cell apoptosis, but also suppressed GC cell growth in vitro and in vivo. Moreover, PITX1 expression was regulated by miR-19a-3p. More importantly, a decreased level of PITX1 protein was correlated with poor GC patient prognosis. Conclusion: Decreased expression of PITX1 predicts shorter overall survival in GC patients. As a transcriptional activator, PITX1 regulates apoptosis-related genes, including PDCD5, during gastric carcinogenesis. These data indicate PDCD5 to be a novel and feasible therapeutic target for GC.

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“…A number of monoclonal antibodies targeting different proteins, including EGFR, PD-1 (CD279), VEGF growth factor family, MET, and IGF-1R, are currently being tested and evaluated in clinical trials ( Table 1) [36][37][38][39].…”

Section: Monoclonal Antibodiesmentioning

confidence: 99%

Clinical Implications of Molecular Heterogeneity of Gastric Cancer

Hudler¹,

Komel²

2017

Gastric Cancer

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Gastric cancer incidence has been steadily declining in countries with low frequencies of gastric carcinoma since early 1930s. In areas with higher incidences, the decline has been less obvious and slower. Nevertheless, gastric adenocarcinoma remains one of the most common causes of cancer-related death worldwide. The poor outcome has been attributed to late detection of the condition, particularly in Americas and Europe, aggressive pathogenesis and lack of symptoms during early stages of the tumor development. In addition, sporadic stomach cancer mostly affects elderly individuals. In the majority of countries with low incidence, the average age at the disease presentation is above 65. Therefore, gastric adenocarcinoma, among other diseases associated with old age, raises health concerns in countries with changing demographic age profiles that show a trend of an increase in the proportion of the population aged over 60. The low 5-year survival rate of patients underscores the critical need for the development of more accurate diagnostic tools and safe targeted chemotherapeutics. However, the heterogeneity of molecular changes represents one of the most pressing issues in the current research of gastric cancer, impeding the translation of genetic aberrations into novel applications for medical practice.

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New advances in targeted gastric cancer treatment

Cited by 81 publications

References 189 publications

DNA hypomethylation promotes invasion and metastasis of gastric cancer cells by regulating the binding of SP1 to the CDCA3 promoter

DNA hypomethylation promotes invasion and metastasis of gastric cancer cells by regulating the binding of SP1 to the CDCA3 promoter

Downregulated PITX1 Modulated by MiR-19a-3p Promotes Cell Malignancy and Predicts a Poor Prognosis of Gastric Cancer by Affecting Transcriptionally Activated PDCD5

Clinical Implications of Molecular Heterogeneity of Gastric Cancer

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