Department of Hepatobiliary-Pancreatic Surgery, Cell Transplantation Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.
School of Medicine, Chengdu, Sichuan, China.
Cancer Med. 2023 Feb;12(3):3786-3796. doi: 10.1002/cam4.5110. Epub 2022 Aug 10.
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.
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.
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.
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.
肝细胞癌（HCC）死亡率高，对化疗耐受。索拉非尼是过去几十年来 HCC 患者的一线治疗选择，但其治疗效果在几乎所有 HCC 患者中都受到限制。
本研究分析了对索拉非尼治疗有不同反应的 HCC 患者的公共组学数据。为了确认整合素 A5 和 B1（ITGA5 和 ITGB1）在索拉非尼耐药中的作用，我们生成了索拉非尼耐药（Sor-R）细胞系和过表达 ITGA5 或 ITGB1 的细胞。通过流式细胞术使用 Hypoxy 探针测量缺氧水平，通过 CD31 和过碘酸希夫染色检测和定量血管生成拟态。
无应答患者的缺氧水平上调，伴有编码细胞外基质成分和血管生成的基因，如 ITGA5 和 ITGB1。构建 Sor-R 肝癌细胞系以测量候选基因的表达和作用。Sor-R 细胞中 ITGA5 和 ITGB1 上调。ITGA5 或 ITGB1 的上调降低了 HepG2 和 Huh7 细胞对索拉非尼的敏感性，加重了缺氧状态，并导致血管拟态形成。
这些发现表明，与缺氧相关的血管拟态解释了 HCC 患者对索拉非尼治疗无反应的原因。ITGA5 和 ITGB1 可能是索拉非尼治疗后 HCC 患者预后的有效预测因子，也为索拉非尼耐药的 HCC 患者提供了新的治疗靶点。
