Identifying therapeutic targets in gastric cancer: the current status and future direction

Yu, Beiqin; Xie, Jingwu

doi:10.1093/abbs/gmv084

Cited by 16 publications

(13 citation statements)

References 78 publications

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“…Chemotherapy with cisplatin and 5-FU has been the first-line treatment option for advanced gastric cancer, but most patients develop cancer relapse after initial treatment. Although the regulatory mechanisms for chemotherapy resistance in gastric cancer have been reported in the last ten years (Yu and Xie, 2016), little data have been linked with the mechanisms to cancer relapse. Our results indicate that the GLI2-ABCG2 signaling axis is an important mechanism regulating side population and 5Fu resistance in gastric cancer cells.…”

Section: Discussionmentioning

confidence: 99%

The role of GLI2 - ABCG2 signaling axis for 5Fu resistance in gastric cancer

Zhang

et al. 2017

Journal of Genetics and Genomics

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Gastric cancer is a leading cause of cancer-related mortality worldwide, and options to treat gastric cancer are limited. Fluorouracil (5Fu)-based chemotherapy is frequently used as a neoadjuvant or an adjuvant agent for gastric cancer therapy. Most patients with advanced gastric cancer eventually succumb to the disease despite the fact that some patients respond initially to chemotherapy. Thus, identifying molecular mechanisms responsible for chemotherapy resistance will help design novel strategies to treat gastric cancer. In this study, we discovered that residual cancer cells following 5Fu treatment have elevated expression of hedgehog target genes GLI1 and GLI2, suggestive of hedgehog (Hh) signaling activation. Hh signaling, a pathway essential for embryonic development, is an important regulator for putative cancer stem cells/ residual cancer cells. We found that high GLI1/GLI2 expression is associated with some features of putative cancer stem cells, such as increased side population. We demonstrated that GLI2 knockdown sensitized gastric cancer cells to 5Fu treatment, decreased ABCG2 expression, and reduced side population. Elevated GLI2 expression is also associated with an increase in tumor sphere size, another marker for putative cancer stem cells. We believe that GLI2 regulates putative cancer stem cells through direct regulation of ABCG2. ABCG2 can rescue the Gli2 shRNA effects in 5Fu response, tumor sphere formation and side population changes, suggesting that ABCG2 is an important mediator for GLI2-associated 5Fu resistance. The relevance of our studies to gastric cancer patient care is reflected by our discovery that high GLI1/GLI2/ABCG2 expression is associated with a high incidence of cancer relapse in two cohorts of gastric cancer patients who underwent chemotherapy (containing 5Fu). Taken together, we have identified a molecular mechanism by which gastric cancer cells gain 5Fu resistance.

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Section: Discussionmentioning

confidence: 99%

The role of GLI2 - ABCG2 signaling axis for 5Fu resistance in gastric cancer

Zhang

et al. 2017

Journal of Genetics and Genomics

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“…GC is the third leading cause of cancer death and remains a major clinical challenge due to its poor prognosis and limited treatment options [13]. Although intensive research has been conducted to detect and validate a variety of molecules associated with GC cell differentiation and proliferation [14], the molecular mechanisms are not fully understood.…”

Section: Discussionmentioning

confidence: 99%

ISL1, a novel regulator ofCCNB1,CCNB2andc-MYCgenes, promotes gastric cancer cell proliferation and tumor growth

et al. 2016

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Islet-1 (ISL1) belongs to the LIM homeodomain transcription factor family, which is specifically expressed in certain tissue types only. Previously, we reported that ISL1 is aberrantly overexpressed in gastric cancer (GC). However, its role in GC is not clear. Here, we report that ISL1 is aberrantly upregulated not only in human gastric carcinoma tissues but also in some GC cell lines. Upregulated ISL1 expression enhanced xenografted gastric carcinoma development, while ISL1 knockdown inhibited GC growth in nude mice. ISL1 overexpression promoted GC cell proliferation, colony formation, and cell growth in soft agar, and facilitated cell cycle transition in GC cells, demonstrated an increase in the proportion of cells in the G2/M and S phases and a decrease in the proportion of cells in the G1 phase. Furthermore, we provide evidence that ISL1 is a novel regulator of the cyclin B1 (CCNB1), cyclin B2 (CCNB2) and c-myc (c-MYC) genes. ISL1 activated the expression of these genes in GC cells by binding to the conserved binding sites on their promoters or enhancers. The expression levels of the genes were decreased in response to ISL1 knockdown. Therefore, ISL1 may serve as a potential therapeutic target in GC.

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“…Furthermore, estimates suggest that the gastric cancer‐related death rate will continue to increase . Thus, there is an urgent need to identify novel biomarkers that could be used to predict prognosis and elucidate the underlying molecular mechanisms …”

Section: Introductionmentioning

confidence: 99%

“…3 Thus, there is an urgent need to identify novel biomarkers that could be used to predict prognosis and elucidate the underlying molecular mechanisms. 4 Ninety years ago, Otto Warburg published a series of works linking metabolism and cancer through enhanced aerobic glycolysis (also known as the Warburg effect) that distinguishes cancer from normal tissues. 5 With further studies, aberrant cancer cell metabolism came to be regarded as one of the hallmarks of cancer.…”

Section: Introductionmentioning

confidence: 99%

CDK2 positively regulates aerobic glycolysis by suppressing SIRT5 in gastric cancer

Zhong

Tang

et al. 2018

Cancer Science

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Although significant progress has been made in the diagnosis and treatment of gastric cancer, the overall survival rate of the disease remains unchanged at approximately 20%‐25%. Thus, there is an urgent need for a better understanding of the molecular biology aspects of the disease in the hope of discovering novel diagnosis and treatment strategies. Recent years have witnessed decisive roles of aberrant cancer cell metabolism in the maintenance of malignant hallmarks of cancers, and cancer cell metabolism has been regarded as a novel target for the treatment of cancer. CDK2, a cell cycle‐dependent kinase that usually regulates cell cycle progression and the DNA damage response, is reported to be upregulated in many cancers. However, little is known about its role in cancer cell metabolism. In the present study, we showed that silencing CDK2 inhibited the aerobic glycolytic capacity of gastric cancer cell lines. Mechanism explorations showed that silencing CDK2 increased expression of the SIRT5 tumor suppressor. In addition, the physiological roles of SIRT5 in the regulation of proliferation and glycolysis were studied in gastric cancer cells. Taken together, the present study uncovered novel roles of the CDK2/SIRT5 axis in gastric cancer and suggests future studies concerning gastric cancer cell metabolism.

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Identifying therapeutic targets in gastric cancer: the current status and future direction

Cited by 16 publications

References 78 publications

The role of GLI2 - ABCG2 signaling axis for 5Fu resistance in gastric cancer

The role of GLI2 - ABCG2 signaling axis for 5Fu resistance in gastric cancer

ISL1, a novel regulator ofCCNB1,CCNB2andc-MYCgenes, promotes gastric cancer cell proliferation and tumor growth

CDK2 positively regulates aerobic glycolysis by suppressing SIRT5 in gastric cancer

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