Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
Ann Surg Oncol. 2013 Dec;20 Suppl 3:S527-36. doi: 10.1245/s10434-013-2945-2. Epub 2013 Jun 9.
Hypoxia inducible factor-1α (HIF-1α) is a major regulator of tumorigenesis in hypoxic conditions and therefore represents a potential therapeutic target in colorectal cancer (CRC). Clinical significance of HIF-1α expression in liver metastases has not been elucidated. Therefore, this study aimed to clarify the clinical significance of HIF-1α expression in colorectal liver metastasis (CRLM).
We retrospectively analyzed 64 patients who underwent curative resection of CRLM from 2000 to 2008. We evaluated HIF-1α expression by immunohistochemical staining and analyzed its association with several clinicopathological characteristics, including vascular endothelial growth factor (VEGF) expression. We analyzed the mutation status of genes involved in CRC (p53, KRAS, BRAF, and PIK3CA). Finally, we compared HIF-1α expression between the primary tumor and the corresponding liver metastases.
We found a significant positive correlation between HIF-1α expression in liver metastases and PIK3CA mutation status (p = 0.019). A significant correlation was also observed between the expressions of HIF-1α and VEGF in liver metastases and primary tumors (p = 0.015, 0.024, respectively). High HIF-1α expression in liver metastases was an independent risk factor for recurrence (p = 0.031).
Our results suggest a possible induction of HIF-1α expression by mutant PIK3CA. The expressions of HIF-1α and VEGF in liver metastases significantly correlated with those in the corresponding primary tumor. Overexpression of HIF-1α was an independent risk factor for recurrence after curative resection of CRLM, suggesting that HIF-1α represents an important candidate for the treatment of CRLM in a subset of patients with high HIF-1α expression.
缺氧诱导因子-1α（HIF-1α）是缺氧条件下肿瘤发生的主要调节剂，因此是结直肠癌（CRC）的潜在治疗靶点。HIF-1α 在肝转移中的表达的临床意义尚未阐明。因此，本研究旨在阐明 HIF-1α 在结直肠癌肝转移（CRLM）中的表达的临床意义。
我们回顾性分析了 2000 年至 2008 年期间接受 CRLM 根治性切除术的 64 例患者。我们通过免疫组织化学染色评估 HIF-1α 的表达，并分析其与包括血管内皮生长因子（VEGF）表达在内的几种临床病理特征的相关性。我们分析了涉及 CRC 的基因（p53、KRAS、BRAF 和 PIK3CA）的突变状态。最后，我们比较了原发肿瘤和相应肝转移灶中 HIF-1α 的表达。
我们发现肝转移灶中 HIF-1α 的表达与 PIK3CA 突变状态之间存在显著的正相关（p = 0.019）。肝转移灶和原发肿瘤中 HIF-1α 和 VEGF 的表达之间也存在显著相关性（p = 0.015，0.024）。肝转移灶中 HIF-1α 的高表达是复发的独立危险因素（p = 0.031）。
我们的结果表明，突变的 PIK3CA 可能诱导 HIF-1α 的表达。肝转移灶中 HIF-1α 和 VEGF 的表达与相应原发肿瘤中的表达显著相关。HIF-1α 的过表达是 CRLM 根治性切除后复发的独立危险因素，这表明 HIF-1α 是高 HIF-1α 表达患者 CRLM 治疗的一个重要候选靶点。
