Intratumor HIF-1α modulates production of a cachectic ligand to cause host wasting
Tumor-host interactions play critical roles in cancer-associated cachexia. Previous studies have identified several cachectic proteins secreted by tumors that impair metabolic homeostasis in multiple organs, leading to host wasting. The molecular mechanisms by which malignant tumors regulate the pro...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-06-01
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| Series: | Cell Insight |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2772892725000215 |
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| author | Gen Xiao Yingge Li Yanhui Hu Kai Tan Mengyang Wang Kerui Zhu Mingkui San Qian Cheng Dilinigeer Tayier Tingting Hu Peixuan Dang Jiaying Li Chen Cheng Norbert Perrimon Zhiyong Yang Wei Song |
| author_facet | Gen Xiao Yingge Li Yanhui Hu Kai Tan Mengyang Wang Kerui Zhu Mingkui San Qian Cheng Dilinigeer Tayier Tingting Hu Peixuan Dang Jiaying Li Chen Cheng Norbert Perrimon Zhiyong Yang Wei Song |
| author_sort | Gen Xiao |
| collection | DOAJ |
| description | Tumor-host interactions play critical roles in cancer-associated cachexia. Previous studies have identified several cachectic proteins secreted by tumors that impair metabolic homeostasis in multiple organs, leading to host wasting. The molecular mechanisms by which malignant tumors regulate the production or secretion of these cachectic proteins, however, still remain largely unknown. In this study, we used different Drosophila cachexia models to investigate how malignant tumors regulate biosynthesis of ImpL2, a conserved cachectic protein that inhibits systemic insulin/IGF signaling and suppresses anabolism of host organs. Through bioinformatic and biochemical analysis, we found that hypoxia-inducible factor HIF-1α/Sima directly binds to the promoter region of ImpL2 gene for the first time, promoting its transcription in both tumors and non-tumor cells. Interestingly, expressing HphA to moderately suppress HIF-1α/Sima activity in adult yki3SA gut tumors or larval scrib1 RasV12 disc tumors sufficiently decreased ImpL2 expression and improved organ wasting, without affecting tumor growth. We further revealed conserved regulatory mechanisms conserved across species, as intratumor HIF-1α enhances the production of IGFBP-5, a mammalian homolog of fly ImpL2, contributing to organ wasting in both tumor-bearing mice and patients. Therefore, our study provides novel insights into the mechanisms by which tumors regulate production of cachectic ligands and the pathogenesis of cancer-induced cachexia. |
| format | Article |
| id | doaj-art-2cd1ff69215647c29e2caee613d9c800 |
| institution | Kabale University |
| issn | 2772-8927 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Insight |
| spelling | doaj-art-2cd1ff69215647c29e2caee613d9c8002025-08-20T03:31:05ZengElsevierCell Insight2772-89272025-06-014310024710.1016/j.cellin.2025.100247Intratumor HIF-1α modulates production of a cachectic ligand to cause host wastingGen Xiao0Yingge Li1Yanhui Hu2Kai Tan3Mengyang Wang4Kerui Zhu5Mingkui San6Qian Cheng7Dilinigeer Tayier8Tingting Hu9Peixuan Dang10Jiaying Li11Chen Cheng12Norbert Perrimon13Zhiyong Yang14Wei Song15Department of Hepatobiliary and Pancreatic Surgery, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, Hubei, China; TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, Hubei, ChinaDepartment of Hepatobiliary and Pancreatic Surgery, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, Hubei, China; TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, Hubei, ChinaDepartment of Genetics, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USADepartment of Hepatobiliary and Pancreatic Surgery, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, Hubei, ChinaDepartment of Hepatobiliary and Pancreatic Surgery, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, Hubei, ChinaDepartment of Hepatobiliary and Pancreatic Surgery, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, Hubei, ChinaDepartment of Hepatobiliary and Pancreatic Surgery, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, Hubei, ChinaDepartment of Hepatobiliary and Pancreatic Surgery, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, Hubei, ChinaDepartment of Genetics, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USADepartment of Hepatobiliary and Pancreatic Surgery, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, Hubei, China; TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, Hubei, ChinaDepartment of Hepatobiliary and Pancreatic Surgery, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, Hubei, China; TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, Hubei, ChinaDepartment of Hepatobiliary and Pancreatic Surgery, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, Hubei, China; TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, Hubei, ChinaDepartment of Hepatobiliary and Pancreatic Surgery, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, Hubei, China; TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, Hubei, ChinaDepartment of Genetics, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USADepartment of Hepatobiliary and Pancreatic Surgery, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, Hubei, China; Corresponding author. Department of Hepatobiliary and Pancreatic Surgery, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, Hubei, China.Department of Hepatobiliary and Pancreatic Surgery, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, Hubei, China; TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, Hubei, China; Corresponding author. TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, Hubei, China.Tumor-host interactions play critical roles in cancer-associated cachexia. Previous studies have identified several cachectic proteins secreted by tumors that impair metabolic homeostasis in multiple organs, leading to host wasting. The molecular mechanisms by which malignant tumors regulate the production or secretion of these cachectic proteins, however, still remain largely unknown. In this study, we used different Drosophila cachexia models to investigate how malignant tumors regulate biosynthesis of ImpL2, a conserved cachectic protein that inhibits systemic insulin/IGF signaling and suppresses anabolism of host organs. Through bioinformatic and biochemical analysis, we found that hypoxia-inducible factor HIF-1α/Sima directly binds to the promoter region of ImpL2 gene for the first time, promoting its transcription in both tumors and non-tumor cells. Interestingly, expressing HphA to moderately suppress HIF-1α/Sima activity in adult yki3SA gut tumors or larval scrib1 RasV12 disc tumors sufficiently decreased ImpL2 expression and improved organ wasting, without affecting tumor growth. We further revealed conserved regulatory mechanisms conserved across species, as intratumor HIF-1α enhances the production of IGFBP-5, a mammalian homolog of fly ImpL2, contributing to organ wasting in both tumor-bearing mice and patients. Therefore, our study provides novel insights into the mechanisms by which tumors regulate production of cachectic ligands and the pathogenesis of cancer-induced cachexia.http://www.sciencedirect.com/science/article/pii/S2772892725000215 |
| spellingShingle | Gen Xiao Yingge Li Yanhui Hu Kai Tan Mengyang Wang Kerui Zhu Mingkui San Qian Cheng Dilinigeer Tayier Tingting Hu Peixuan Dang Jiaying Li Chen Cheng Norbert Perrimon Zhiyong Yang Wei Song Intratumor HIF-1α modulates production of a cachectic ligand to cause host wasting Cell Insight |
| title | Intratumor HIF-1α modulates production of a cachectic ligand to cause host wasting |
| title_full | Intratumor HIF-1α modulates production of a cachectic ligand to cause host wasting |
| title_fullStr | Intratumor HIF-1α modulates production of a cachectic ligand to cause host wasting |
| title_full_unstemmed | Intratumor HIF-1α modulates production of a cachectic ligand to cause host wasting |
| title_short | Intratumor HIF-1α modulates production of a cachectic ligand to cause host wasting |
| title_sort | intratumor hif 1α modulates production of a cachectic ligand to cause host wasting |
| url | http://www.sciencedirect.com/science/article/pii/S2772892725000215 |
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