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      Downregulation of miR203 induces overexpression of PIK3CA and predicts poor prognosis of gastric cancer patients

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          Abstract

          Background

          Despite advances in clinical therapies and technologies, the prognosis for patients with gastric cancer is still poor. The aim of this study is to investigate new predictive markers for prognosis of gastric cancer.

          Methods

          In this study, we evaluated the expression pattern of PIK3CA in 107 gastric cancer specimens and their adjacent nontumorous tissues. PIK3CA siRNA was synthesized and transfected into gastric cancer cell lines. Colony formation and MTT assays were employed to analyze the cell proliferation. PIK3CA expression was examined by using immunohistochemical analysis and Western blot assay. Transwell invasion assay was used to detect the invasion capability of the cells. Luciferase activity was examined by using 3′-untranslated region luciferase reporter assays.

          Results

          We observed that PIK3CA was significantly upregulated in gastric cancer tissues. High expression level of PIK3CA was detectable in 48 (44.86%) of the gastric cancer specimens, and correlated with poor prognosis. In addition, our study indicated that miR203 inhibits cell proliferation and invasion via directly targeting and suppressing the PIK3CA expression. MiR203 expression is downregulated in gastric cancer tissues. Moreover, low expression level of miR203 predicted poor prognosis of gastric patients and induced overexpression of PIK3CA. Our further study also reported that overexpression of miR203 inhibited phosphorylation of AKT, while cotransfection of PIK3CA reversed the effect of miR203.

          Conclusion

          Our study suggested a miR203- PIK3CA-AKT signaling pathway in gastric cancer cells. This signaling pathway might play an important role in gastric cancer genesis and development.

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          Most cited references 17

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          MicroRNA-140-5p suppresses tumor growth and metastasis by targeting transforming growth factor β receptor 1 and fibroblast growth factor 9 in hepatocellular carcinoma.

          By comparing the expression profiles of microRNAs (miRNAs) in different hepatocellular carcinoma (HCC) subtypes, we identified miR-140-5p as an HCC-related miRNA. We found that miR-140-5p was significantly decreased in HCC tissues and all of six liver cancer cell lines examined and its expression levels were correlated with multiple nodules, vein invasion, capsular formation, and differentiation, as well as overall and disease-free survival of HCC. We also found that miR-140-5p suppressed HCC cell proliferation and HCC metastasis. Multipathway reporter arrays suggested that miR-140-5p inhibited transforming growth factor β (TGF-β) and mitogen-activated protein kinase / extracellular signal-regulated kinase (MAPK/ERK) signaling. TGFB receptor 1 (TGFBR1) and fibroblast growth factor 9 (FGF9) were then characterized as the direct targets for miR-140-5p after it was found that ectopic miR-140-5p expression suppressed TGFBR1 and FGF9 expression. Silencing TGFBR1 and FGF9 by small interfering RNA (siRNA) resembled the phenotype resulting from ectopic miR-140-5p expression, while overexpression of TGFBR1 and FGF9 attenuated the effect of miR-140-5p on HCC growth and metastasis. These data elucidated a tumor suppressor role for miR-140-5p in HCC development and progression with therapeutic potential. Our correlation studies in clinical HCC samples further suggest that miR-140-5p could be a valuable biomarker for HCC prognosis. Copyright © 2013 American Association for the Study of Liver Diseases.
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            Report of incidence and mortality in China cancer registries, 2009.

            The National Central Cancer Registry (NCCR) collected cancer registration data in 2009 from local cancer registries in 2012, and analyzed to describe cancer incidence and mortality in China. On basis of the criteria of data quality from NCCR, data submitted from 104 registries were checked and evaluated. There were 72 registries' data qualified and accepted for cancer registry annual report in 2012. Descriptive analysis included incidence and mortality stratified by area (urban/rural), sex, age group and cancer site. The top 10 common cancers in different groups, proportion and cumulative rates were also calculated. Chinese population census in 1982 and Segi's population were used for age-standardized incidence/mortality rates. All 72 cancer registries covered a total of 85,470,522 population (57,489,009 in urban and 27,981,513 in rural areas). The total new cancer incident cases and cancer deaths were 244,366 and 154,310, respectively. The morphology verified cases accounted for 67.23%, and 3.14% of incident cases only had information from death certifications. The crude incidence rate in Chinese cancer registration areas was 285.91/100,000 (males 317.97/100,000, females 253.09/100,000), age-standardized incidence rates by Chinese standard population (ASIRC) and by world standard population (ASIRW) were 146.87/100,000 and 191.72/100,000 with the cumulative incidence rate (0-74 age years old) of 22.08%. The cancer incidence and ASIRC were 303.39/100,000 and 150.31/100,000 in urban areas whereas in rural areas, they were 249.98/100,000 and 139.68/100,000, respectively. The cancer mortality in Chinese cancer registration areas was 180.54/100,000 (224.20/100,000 in males and 135.85/100,000 in females), age-standardized mortality rates by Chinese standard population (ASMRC) and by world standard population (ASMRW) were 85.06/100,000 and 115.65/100,000, and the cumulative incidence rate (0-74 age years old) was 12.94%. The cancer mortality and ASMRC were 181.86/100,000 and 80.86/100,000 in urban areas, whereas in rural areas, they were 177.83/100,000 and 94.40/100,000 respectively. Lung cancer, gastric cancer, colorectal cancer, liver cancer, esophageal cancer, pancreas cancer, encephaloma, lymphoma, female breast cancer and cervical cancer, were the most common cancers, accounting for 75% of all cancer cases in urban and rural areas. Lung cancer, gastric cancer, liver cancer, esophageal cancer, colorectal cancer, pancreatic cancer, breast cancer, encephaloma, leukemia and lymphoma accounted for 80% of all cancer deaths. The cancer spectrum showed difference between urban and rural areas, males and females. The main cancers in rural areas were cancers of the stomach, followed by esophageal cancer, lung cancer, liver cancer and colorectal cancer, whereas the main cancer in urban areas was lung cancer, followed by liver cancer, gastric cancer and colorectal cancer. The coverage of cancer registration population has been increasing and data quality is improving. As the basis of cancer control program, cancer registry plays an important role in making anti-cancer strategy in medium and long term. As cancer burdens are different between urban and rural areas in China, prevention and control should be implemented based on practical situation.
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              Prognostic role of PIK3CA mutation in colorectal cancer: cohort study and literature review.

              Mutations in PIK3CA [the gene encoding the p110α catalytic subunit of phosphatidylinositide-3-kinase (PI3K)] play an important role in colorectal carcinogenesis. Experimental evidence suggests that PIK3CA exon 9 and exon 20 mutations trigger different biologic effects, and that concomitant mutations in both exons 9 and 20 synergistically enhance tumorigenic effects. Thus, we hypothesized that PIK3CA exon 9 and exon 20 mutations might have differential effects on clinical outcome in colorectal cancer, and that concomitant PIK3CA exon 9 and 20 mutations might confer aggressive tumor behavior. We sequenced PIK3CA by pyrosequencing in 1,170 rectal and colon cancers in two prospective cohort studies, and found 189 (16%) PIK3CA mutated tumors. Mortality HR according to PIK3CA status was computed using Cox proportional hazards model, adjusting for clinical and molecular features, including microsatellite instability, CpG island methylator phenotype, LINE-1 methylation, and BRAF and KRAS mutations. Compared with PIK3CA wild-type cases, patients with concomitant PIK3CA mutations in exons 9 and 20 experienced significantly worse cancer-specific survival [log-rank P = 0.031; multivariate HR = 3.51; 95% confidence interval (CI): 1.28-9.62] and overall survival (log-rank P = 0.0008; multivariate HR = 2.68; 95% CI: 1.24-5.77). PIK3CA mutation in either exon 9 or 20 alone was not significantly associated with patient survival. No significant interaction of PIK3CA mutation with BRAF or KRAS mutation was observed in survival analysis. Coexistence of PIK3CA (the PI3K p110α subunit) exon 9 and 20 mutations, but not PIK3CA mutation in either exon 9 or 20 alone, is associated with poor prognosis of colorectal cancer patients. ©2012 AACR.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2015
                16 July 2015
                : 9
                : 3607-3616
                Affiliations
                [1 ]Department of Oncology, The fifth affiliated hospital of Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China
                [2 ]Department of radiotherapy, Affiliated Cancer Hospital of Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China
                Author notes
                Correspondence: Xinke Zhou, The Fifth Affiliated Hospital of Guangzhou Medical University, 621 Harbor Road, Guangzhou, Guangdong 510700, People’s Republic of China, Tel +86 20 8228 5847, Fax +86 20 8228 9522, Email zxkstarr@ 123456yeah.net
                [*]

                These authors contributed equally to this work

                Article
                dddt-9-3607
                10.2147/DDDT.S85525
                4509530
                © 2015 Liang et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine

                akt, gastric cancer, mir203, pik3ca, prognosis

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