Browsing by Author "Yu, Beiqin"

Now showing 1 - 7 of 7
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    Functional significance of Hippo/YAP signaling for drug resistance in colorectal cancer
    (Wiley, 2018) Song, Ruolan; Gu, Dongsheng; Zhang, Lining; Zhang, Xiaoli; Yu, Beiqin; Liu, Bingya; Xie, Jingwu; Pediatrics, School of Medicine
    Colorectal cancer is a leading cause of cancer‐related death worldwide. While early stage colorectal cancer can be removed by surgery, patients with advanced disease are treated by chemotherapy, with 5‐Fluorouracil (5‐FU) as a main ingredient. However, most patients with advanced colorectal cancer eventually succumb to the disease despite some responded initially. Thus, identifying molecular mechanisms responsible for drug resistance will help design novel strategies to treat colorectal cancer. In this study, we analyzed an acquired 5‐FU resistant cell line, LoVo‐R, and determined that elevated expression of YAP target genes is a major alteration in the 5‐FU resistant cells. Hippo/YAP signaling, a pathway essential for cell polarity, is an important regulator for tissue homeostasis, organ size, and stem cells. We demonstrated that knockdown of YAP1 sensitized LoVo‐R cells to 5‐FU treatment in cultured cells and in mice. The relevance of our studies to colorectal cancer patients is reflected by our discovery that high expression of YAP target genes in the tumor was associated with an increased risk of cancer relapse and poor survival in a larger cohort of colorectal cancer patients who underwent 5‐FU‐related chemotherapy. Taken together, we demonstrate a critical role of YAP signaling for drug resistance in colorectal cancer.
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    GLI1-mediated regulation of side population is responsible for drug resistance in gastric cancer
    (Impact Journals, 2017-04-18) Yu, Beiqin; Gu, Dongsheng; Zhang, Xiaoli; Li, Jianfang; Liu, Bingya; Xie, Jingwu; Pediatrics, School of Medicine
    Gastric cancer is the third leading cause of cancer-related mortality worldwide. Chemotherapy is frequently used for gastric cancer treatment. Most patients with advanced gastric cancer eventually succumb to the disease despite some patients responded initially to chemotherapy. Thus, identifying molecular mechanisms responsible for cancer relapse following chemotherapy will help design new ways to treat gastric cancer. In this study, we revealed that the residual cancer cells following treatment with chemotherapeutic reagent cisplatin have elevated expression of hedgehog target genes GLI1, GLI2 and PTCH1, suggestive of hedgehog signaling activation. We showed that GLI1 knockdown sensitized gastric cancer cells to CDDP whereas ectopic GLI1 expression decreased the sensitivity. Further analyses indicate elevated GLI1 expression is associated with an increase in tumor sphere formation, side population and cell surface markers for putative cancer stem cells. We have evidence to support that GLI1 is critical for maintenance of putative cancer stem cells through direct regulation of ABCG2. In fact, GLI1 protein was shown to be associated with the promoter fragment of ABCG2 through a Gli-binding consensus site in gastric cancer cells. Disruption of ABCG2 function, through ectopic expression of an ABCG2 dominant negative construct or a specific ABCG2 inhibitor, increased drug sensitivity of cancer cells both in culture and in mice. The relevance of our studies to gastric cancer patient care is reflected by our discovery that high ABCG2 expression was associated with poor survival in the gastric cancer patients who underwent chemotherapy. Taken together, we have identified a molecular mechanism by which gastric cancer cells gain chemotherapy resistance.
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    Identifying therapeutic targets in gastric cancer: the current status and future direction
    (Oxford University Press, 2016-01) Yu, Beiqin; Xie, Jingwu; Department of Pediatrics, IU School of Medicine
    Gastric cancer is the third leading cause of cancer-related death worldwide. Our basic understanding of gastric cancer biology falls behind that of many other cancer types. Current standard treatment options for gastric cancer have not changed for the last 20 years. Thus, there is an urgent need to establish novel strategies to treat this deadly cancer. Successful clinical trials with Gleevec in CML and gastrointestinal stromal tumors have set up an example for targeted therapy of cancer. In this review, we will summarize major progress in classification, therapeutic options of gastric cancer. We will also discuss molecular mechanisms for drug resistance in gastric cancer. In addition, we will attempt to propose potential future directions in gastric cancer biology and drug targets.
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    Regulation of pancreatic cancer metastasis through the Gli2-YAP1 axis via regulation of anoikis
    (Elsevier, 2022-05-24) Yu, Beiqin; Gu, Dongsheng; Zhang, Xiaoli; Liu, Bingya; Xie, Jingwu; Pediatrics, School of Medicine
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    The role of GLI-SOX2 signaling axis for gemcitabine resistance in pancreatic cancer
    (Springer Nature, 2019-03) Jia, Yanfei; Gu, Dongsheng; Wan, Jun; Yu, Beiqin; Zhang, Xiaoli; Chiorean, E. Gabriela; Wang, Yunshan; Xie, Jingwu; Pediatrics, School of Medicine
    Pancreatic cancer, mostly pancreatic ductal adenocarcinomas (PDAC), is one of the most lethal cancers, with a dismal median survival around 8 months. PDAC is notoriously resistant to chemotherapy. Thus far, numerous attempts using novel targeted therapies and immunotherapies yielded limited clinical benefits for pancreatic cancer patients. It is hoped that delineating the molecular mechanisms underlying drug resistance in pancreatic cancer may provide novel therapeutic options. Using acquired gemcitabine resistant pancreatic cell lines, we revealed an important role of the GLI-SOX2 signaling axis for regulation of gemcitabine sensitivity in vitro and in animal models. Down-regulation of GLI transcriptional factors (GLI1 or GLI2), but not SMO signaling inhibition, reduces tumor sphere formation, a characteristics of tumor initiating cell (TIC). Down-regulation of GLI transcription factors also decreased expression of TIC marker CD24. Similarly, high SOX2 expression is associated with gemcitabine resistance whereas down-regulation of SOX2 sensitizes pancreatic cancer cells to gemcitabine treatment. We further revealed that elevated SOX2 expression is associated with an increase in GLI1 or GLI2 expression. Our ChIP assay revealed that GLI proteins are associated with a putative Gli binding site within the SOX2 promoter, suggesting a more direct regulation of SOX2 by GLI transcription factors. The relevance of our findings to human disease was revealed in human cancer specimens. We found that high SOX2 protein expression is associated with frequent tumor relapse and poor survival in stage II PDAC patients (all of them underwent gemcitabine treatment), indicating that reduced SOX2 expression or down-regulation of GLI transcription factors may be effective in sensitizing pancreatic cancer cells to gemcitabine treatment.
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    The role of GLI1 for 5-Fu resistance in colorectal cancer
    (BioMed Central, 2017-04-13) Zhang, Lining; Song, Ruolan; Gu, Dongsheng; Zhang, Xiaoli; Yu, Beiqin; Liu, Bingya; Xie, Jingwu; Pediatrics, School of Medicine
    Colorectal cancer is a leading cause of cancer-related mortality worldwide, with Fluorouracil (5-FU)-based chemotherapy as the major treatment for advanced disease. Many patients with advanced colorectal cancer eventually succumb to the disease despite some patients responded initially to chemotherapy. Thus, identifying molecular mechanisms responsible for chemotherapy resistance will help design novel strategies to treat colorectal cancer. In this study, we established an acquired 5-FU resistant cell line, LoVo-R, from LoVo cells. Through exome sequencing, we discovered that elevated GLI1 signaling axis is a major genetic alteration in the 5-FU resistant cells. Hh signaling, a pathway essential for embryonic development, is an important regulator for residual cancer cells. We demonstrated that knockdown of GLI1 or GLI2 sensitized LoVo-R cells to 5-FU treatment, reduced cell invasiveness. The relevance of our studies to colorectal cancer patients is reflected by our discovery that high expression of GLI1 signaling molecules was associated with a high incidence of cancer relapse and a shorter survival in a larger cohort of colorectal cancer patients who underwent chemotherapy (containing 5-FU). Taken together, our data demonstrate the critical role of the GLI1 signaling axis for 5-FU resistance in colorectal cancer.
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    The role of GLI2-ABCG2 signaling axis for 5Fu resistance in gastric cancer
    (Elsevier, 2017-08-20) Yu, Beiqin; Gu, Dongsheng; Zhang, Xiaoli; Liu, Bingya; Xie, Jingwu; Pediatrics, School of Medicine
    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 (Hg) target genes GLI1 and GLI2, suggestive of 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.