Nakamura Jun, Kitajima Yoshihiko, Kai Keita, Mitsuno Mayumi, Ide Takao, Hashiguchi Kazuyoshi, Hiraki Masatsugu, Miyazaki Kohji
Department of Surgery, Saga University Faculty of Medicine, Nabeshima, Saga 849-8501, Japan.
Oncol Rep. 2009 Oct;22(4):693-9. doi: 10.3892/or_00000489.
Hypoxia frequently occurs in various solid tumors, thereby accelerating cancer progression and treatment resistance. Hypoxia-inducible factor-1alpha (HIF-1alpha) plays a central role in tumor hypoxia by up-regulating the gene expression related to angiogenesis, cancer invasion and anti-apoptosis. The present study immunohistochemically investigated HIF-1alpha expression in 63 gastric cancer specimens. Those specimens were obtained from 44 patients that received 5-FU chemotherapy post-operatively whereas the remaining 19 patients did not. The immunostaining pattern of HIF-1alpha was classified into 3 patterns: diffuse-positive within the tumor (DP), positive at the invasive front of the tumor (FP) and negative (N). Thirty-six of 63 (57.1%) patients exhibited DP, 24 (38.1%) revealed FP and the remaining 3 (4.8%) patients were judged as N. The HIF-1alpha expression pattern grouped into DP and FP/N correlated with the clinicopathological factors and survival. As a result, the HIF-1alpha expression did not show a significant correlation with the clinicopathological factors, such as the depth of invasion, lymph node metastasis and tumor stage, nor patient survival in the 63 patients. However, in the 44 patients that underwent chemotherapy, patients with the FP/N pattern showed longer survival than those with the DP pattern. On the other hand, no significant difference in survival was found between the 2 patterns among 19 patients without the chemotherapy. These results indicated that the diffuse expression of HIF-1alpha in gastric tumors might lead to drug resistance against adjuvant chemotherapy using 5-FU. In conclusion, the assessment of the HIF-1alpha expression in the resected tissues might predict the drug response to adjuvant 5-FU chemotherapy in advanced gastric cancer patients.
缺氧在各种实体瘤中频繁发生，从而加速癌症进展和治疗抵抗。缺氧诱导因子-1α（HIF-1α）通过上调与血管生成、癌症侵袭和抗凋亡相关的基因表达，在肿瘤缺氧中起核心作用。本研究采用免疫组织化学方法检测了63例胃癌标本中HIF-1α的表达。这些标本来自44例术后接受5-氟尿嘧啶化疗的患者，其余19例患者未接受化疗。HIF-1α的免疫染色模式分为3种：肿瘤内弥漫阳性（DP）、肿瘤侵袭前沿阳性（FP）和阴性（N）。63例患者中，36例（57.1%）表现为DP，24例（38.1%）为FP，其余3例（4.8%）为N。HIF-1α表达模式分为DP和FP/N与临床病理因素及生存率相关。结果显示，HIF-1α表达与63例患者的临床病理因素，如侵袭深度、淋巴结转移和肿瘤分期，以及患者生存率均无显著相关性。然而，在44例接受化疗的患者中，FP/N模式的患者比DP模式的患者生存期更长。另一方面，19例未接受化疗的患者中，两种模式的生存率无显著差异。这些结果表明，胃癌中HIF-1α的弥漫性表达可能导致对5-氟尿嘧啶辅助化疗的耐药性。总之，评估切除组织中HIF-1α的表达可能预测晚期胃癌患者对5-氟尿嘧啶辅助化疗的药物反应。
