Expression of asporin reprograms cancer cells to acquire resistance to oxidative stress
| العنوان: | Expression of asporin reprograms cancer cells to acquire resistance to oxidative stress |
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| المؤلفون: | Satoru Yamada, Kurara Takagane, Masakazu Yashiro, Kazuyoshi Yanagihara, Go Itoh, Sei Kuriyama, Yuto Sasaki, Masamitsu Tanaka, Shinya Murakami, Takumi Konno |
| المصدر: | Cancer Science |
| بيانات النشر: | John Wiley and Sons Inc, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | rac1 GTP-Binding Protein, 0301 basic medicine, Cancer Research, Apoptosis, Mice, 0302 clinical medicine, Cancer-Associated Fibroblasts, Cell, Molecular, and Stem Cell Biology, Cell Movement, oxidative stress, HIF1α, Mice, Knockout, Extracellular Matrix Proteins, education.field_of_study, biology, Chemistry, Stomach, Cell migration, ROS, General Medicine, Mitochondria, Up-Regulation, Hyaluronan Receptors, Matrix Metalloproteinase 9, Oncology, Gene Knockdown Techniques, 030220 oncology & carcinogenesis, Original Article, Lactate dehydrogenase A, 03 medical and health sciences, Gastrectomy, Stomach Neoplasms, Cell Line, Tumor, Animals, Humans, Neoplasm Invasiveness, education, HIF1 alpha, gastric cancer, Carcinoma, CD44, Asporin, Original Articles, Hypoxia-Inducible Factor 1, alpha Subunit, Xenograft Model Antitumor Assays, Glucose, 030104 developmental biology, Anaerobic glycolysis, Cell culture, Tumor progression, Cancer cell, Cancer research, biology.protein, asporin, Reactive Oxygen Species |
| الوصف: | Asporin (ASPN), a small leucine‐rich proteoglycan expressed predominantly by cancer associated fibroblasts (CAFs), plays a pivotal role in tumor progression. ASPN is also expressed by some cancer cells, but its biological significance is unclear. Here, we investigated the effects of ASPN expression in gastric cancer cells. Overexpression of ASPN in 2 gastric cancer cell lines, HSC‐43 and 44As3, led to increased migration and invasion capacity, accompanied by induction of CD44 expression and activation of Rac1 and MMP9. ASPN expression increased resistance of HSC‐43 cells to oxidative stress by reducing the amount of mitochondrial reactive oxygen species. ASPN induced expression of the transcription factor HIF1α and upregulated lactate dehydrogenase A (LDHA) and PDH‐E1α, suggesting that ASPN reprograms HSC‐43 cells to undergo anaerobic glycolysis and suppresses ROS generation in mitochondria, which has been observed in another cell line HSC‐44PE. By contrast, 44As3 cells expressed high levels of HIF1α in response to oxidant stress and escaped apoptosis regardless of ASPN expression. Examination of xenografts in the gastric wall of ASPN–/– mice revealed that growth of HSC‐43 tumors with increased micro blood vessel density was significantly accelerated by ASPN; however, ASPN increased the invasion depth of both HSC‐43 and 44As3 tumors. These results suggest that ASPN has 2 distinct effects on cancer cells: HIF1α‐mediated resistance to oxidative stress via reprogramming of glucose metabolism, and activation of CD44‐Rac1 and MMP9 to promote cell migration and invasion. Therefore, ASPN may be a new therapeutic target in tumor fibroblasts and cancer cells in some gastric carcinomas. We demonstrate the importance of ASPN‐mediated resistance of tumor cells to oxidative stress. ASPN expression increased the levels of HIF1a, which shifted glucose metabolism to anaerobic glycolysis and reduced the amount of mitochondrial reactive oxygen species (mtROS), thereby attenuating ROS‐induced apoptosis. |
| اللغة: | English |
| تدمد: | 1347-9032 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::faadab844a0209e0f7eb2acd7b215f62Test http://hdl.handle.net/10295/00006173Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....faadab844a0209e0f7eb2acd7b215f62 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 13479032 |
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