ITGA5 and ITGB1 contribute to Sorafenib resistance by promoting vasculogenic mimicry formation in hepatocellular carcinoma
Abstract Background Hepatocellular carcinoma (HCC) is labeled with high mortality and tolerance to chemotherapy. Sorafenib has been the first‐line treatment option in HCC patients for past decades, while the therapeutic effect was limited in almost HCC patients. Methods In this study, we analyzed pu...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-02-01
|
| Series: | Cancer Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/cam4.5110 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850268776613806080 |
|---|---|
| author | Ying Shi Jin Shang Yan Li Deyuan Zhong Zilong Zhang Qinyan Yang Chunyou Lai Tianhang Feng Yutong Yao Xiaolun Huang |
| author_facet | Ying Shi Jin Shang Yan Li Deyuan Zhong Zilong Zhang Qinyan Yang Chunyou Lai Tianhang Feng Yutong Yao Xiaolun Huang |
| author_sort | Ying Shi |
| collection | DOAJ |
| description | Abstract Background Hepatocellular carcinoma (HCC) is labeled with high mortality and tolerance to chemotherapy. Sorafenib has been the first‐line treatment option in HCC patients for past decades, while the therapeutic effect was limited in almost HCC patients. Methods In this study, we analyzed public omics data of HCC patients with different responses to Sorafenib treatment. To confirm the role of integrins A5 and B1 (ITGA5 and ITGB1) in Sorafenib resistance, we generated the Sorafenib‐resistant (Sor‐R) cell lines and cells overexpressing ITGA5 or ITGB1. Hypoxia level was measured using Hypoxy probe by flow cytometry, while vasculogenic mimicry was detected and quantified by CD31 and periodic acid schiff staining. Results Hypoxia was upregulated in non‐responsive patients, accompanied with genes involved in encoding extracellular matrix components and angiogenesis such as ITGA5 and ITGB1. Sor‐R hepatoma cell lines were constructed to measure expression and role of candidate genes. ITGA5 and ITGB1 were augmented in Sor‐R cells. Upregulation of ITGA5 or ITGB1 reduced the sensitivity to Sorafenib in HepG2 and Huh7 cells, aggravated the hypoxic condition and resulted in formation of vascular mimicry. Conclusions These findings suggested that hypoxia associated vascular mimicry account for non‐response to Sorafenib treatment in HCC patients. ITGA5 and ITGB1 may serve as effective predictors of HCC patients' outcome after Sorafenib treatment, which also provides a new target for HCC patients resistant to Sorafenib. |
| format | Article |
| id | doaj-art-a7517ee2683948cfb6a94e4d3dd7a665 |
| institution | OA Journals |
| issn | 2045-7634 |
| language | English |
| publishDate | 2023-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Cancer Medicine |
| spelling | doaj-art-a7517ee2683948cfb6a94e4d3dd7a6652025-08-20T01:53:22ZengWileyCancer Medicine2045-76342023-02-011233786379610.1002/cam4.5110ITGA5 and ITGB1 contribute to Sorafenib resistance by promoting vasculogenic mimicry formation in hepatocellular carcinomaYing Shi0Jin Shang1Yan Li2Deyuan Zhong3Zilong Zhang4Qinyan Yang5Chunyou Lai6Tianhang Feng7Yutong Yao8Xiaolun Huang9Department of Hepatobiliary‐Pancreatic Surgery, Cell Transplantation Center, Sichuan Provincial People's Hospital University of Electronic Science and Technology of China Chengdu Sichuan ChinaDepartment of Hepatobiliary‐Pancreatic Surgery, Cell Transplantation Center, Sichuan Provincial People's Hospital University of Electronic Science and Technology of China Chengdu Sichuan ChinaDepartment of Hepatobiliary‐Pancreatic Surgery, Cell Transplantation Center, Sichuan Provincial People's Hospital University of Electronic Science and Technology of China Chengdu Sichuan ChinaDepartment of Hepatobiliary‐Pancreatic Surgery, Cell Transplantation Center, Sichuan Provincial People's Hospital University of Electronic Science and Technology of China Chengdu Sichuan ChinaDepartment of Hepatobiliary‐Pancreatic Surgery, Cell Transplantation Center, Sichuan Provincial People's Hospital University of Electronic Science and Technology of China Chengdu Sichuan ChinaDepartment of Hepatobiliary‐Pancreatic Surgery, Cell Transplantation Center, Sichuan Provincial People's Hospital University of Electronic Science and Technology of China Chengdu Sichuan ChinaDepartment of Hepatobiliary‐Pancreatic Surgery, Cell Transplantation Center, Sichuan Provincial People's Hospital University of Electronic Science and Technology of China Chengdu Sichuan ChinaDepartment of Hepatobiliary‐Pancreatic Surgery, Cell Transplantation Center, Sichuan Provincial People's Hospital University of Electronic Science and Technology of China Chengdu Sichuan ChinaDepartment of Hepatobiliary‐Pancreatic Surgery, Cell Transplantation Center, Sichuan Provincial People's Hospital University of Electronic Science and Technology of China Chengdu Sichuan ChinaDepartment of Hepatobiliary‐Pancreatic Surgery, Cell Transplantation Center, Sichuan Provincial People's Hospital University of Electronic Science and Technology of China Chengdu Sichuan ChinaAbstract Background Hepatocellular carcinoma (HCC) is labeled with high mortality and tolerance to chemotherapy. Sorafenib has been the first‐line treatment option in HCC patients for past decades, while the therapeutic effect was limited in almost HCC patients. Methods In this study, we analyzed public omics data of HCC patients with different responses to Sorafenib treatment. To confirm the role of integrins A5 and B1 (ITGA5 and ITGB1) in Sorafenib resistance, we generated the Sorafenib‐resistant (Sor‐R) cell lines and cells overexpressing ITGA5 or ITGB1. Hypoxia level was measured using Hypoxy probe by flow cytometry, while vasculogenic mimicry was detected and quantified by CD31 and periodic acid schiff staining. Results Hypoxia was upregulated in non‐responsive patients, accompanied with genes involved in encoding extracellular matrix components and angiogenesis such as ITGA5 and ITGB1. Sor‐R hepatoma cell lines were constructed to measure expression and role of candidate genes. ITGA5 and ITGB1 were augmented in Sor‐R cells. Upregulation of ITGA5 or ITGB1 reduced the sensitivity to Sorafenib in HepG2 and Huh7 cells, aggravated the hypoxic condition and resulted in formation of vascular mimicry. Conclusions These findings suggested that hypoxia associated vascular mimicry account for non‐response to Sorafenib treatment in HCC patients. ITGA5 and ITGB1 may serve as effective predictors of HCC patients' outcome after Sorafenib treatment, which also provides a new target for HCC patients resistant to Sorafenib.https://doi.org/10.1002/cam4.5110drug resistancehepatocellular carcinomahypoxiaintegrinsorafenibvascular mimicry |
| spellingShingle | Ying Shi Jin Shang Yan Li Deyuan Zhong Zilong Zhang Qinyan Yang Chunyou Lai Tianhang Feng Yutong Yao Xiaolun Huang ITGA5 and ITGB1 contribute to Sorafenib resistance by promoting vasculogenic mimicry formation in hepatocellular carcinoma Cancer Medicine drug resistance hepatocellular carcinoma hypoxia integrin sorafenib vascular mimicry |
| title | ITGA5 and ITGB1 contribute to Sorafenib resistance by promoting vasculogenic mimicry formation in hepatocellular carcinoma |
| title_full | ITGA5 and ITGB1 contribute to Sorafenib resistance by promoting vasculogenic mimicry formation in hepatocellular carcinoma |
| title_fullStr | ITGA5 and ITGB1 contribute to Sorafenib resistance by promoting vasculogenic mimicry formation in hepatocellular carcinoma |
| title_full_unstemmed | ITGA5 and ITGB1 contribute to Sorafenib resistance by promoting vasculogenic mimicry formation in hepatocellular carcinoma |
| title_short | ITGA5 and ITGB1 contribute to Sorafenib resistance by promoting vasculogenic mimicry formation in hepatocellular carcinoma |
| title_sort | itga5 and itgb1 contribute to sorafenib resistance by promoting vasculogenic mimicry formation in hepatocellular carcinoma |
| topic | drug resistance hepatocellular carcinoma hypoxia integrin sorafenib vascular mimicry |
| url | https://doi.org/10.1002/cam4.5110 |
| work_keys_str_mv | AT yingshi itga5anditgb1contributetosorafenibresistancebypromotingvasculogenicmimicryformationinhepatocellularcarcinoma AT jinshang itga5anditgb1contributetosorafenibresistancebypromotingvasculogenicmimicryformationinhepatocellularcarcinoma AT yanli itga5anditgb1contributetosorafenibresistancebypromotingvasculogenicmimicryformationinhepatocellularcarcinoma AT deyuanzhong itga5anditgb1contributetosorafenibresistancebypromotingvasculogenicmimicryformationinhepatocellularcarcinoma AT zilongzhang itga5anditgb1contributetosorafenibresistancebypromotingvasculogenicmimicryformationinhepatocellularcarcinoma AT qinyanyang itga5anditgb1contributetosorafenibresistancebypromotingvasculogenicmimicryformationinhepatocellularcarcinoma AT chunyoulai itga5anditgb1contributetosorafenibresistancebypromotingvasculogenicmimicryformationinhepatocellularcarcinoma AT tianhangfeng itga5anditgb1contributetosorafenibresistancebypromotingvasculogenicmimicryformationinhepatocellularcarcinoma AT yutongyao itga5anditgb1contributetosorafenibresistancebypromotingvasculogenicmimicryformationinhepatocellularcarcinoma AT xiaolunhuang itga5anditgb1contributetosorafenibresistancebypromotingvasculogenicmimicryformationinhepatocellularcarcinoma |