Department of Gynecology and Obstetrics, Renmin Hospital of Wuhan University, Wuhan 430062, PR China.
Ann Diagn Pathol. 2013 Jun;17(3):305-11. doi: 10.1016/j.anndiagpath.2012.12.002. Epub 2013 Feb 1.
The objective of this study is to explore the role of hypoxia inducible factor-1 (HIF-1) in glycolysis activity and its relationship with malignant biologic behaviors of cervical cancer. Immunohistochemistry was performed to study the protein expression and distribution of HIF-1α and glucose transport protein 1 (GLUT1) in cervical tissue of 158 cases, including 28 with normal cervical epithelium, 32 with cervical intraepithelial neoplasia, and 98 with invasive cervical cancer. Cobalt(II) chloride was used to induce hypoxia in Hela and Siha cells; the biologic behaviors of cells cultured in normal or hypoxic environments were monitored by colorimetric, Transwell, flow cytometry, and enzyme-linked immunosorbent assay; immunocytochemistry, Western blot, and reverse transcription-polymerase chain reaction were used to observe gene and protein expression of HIF-1α, GLUT1, and hexokinase II in cell lines during normoxia and hypoxia. The expression of HIF-1α and GLUT1 gradually increased from normal cervical tissue to cervical intraepithelial neoplasia, then to cervical cancer. There were significant differences among these groups (P < .05). HIF-1α was strongly associated with pathologic differentiation, clinic stage, magnitude of lesions, and patient age, whereas GLUT1 was associated with lymphatic metastasis (P < .05). HIF-1α was strongly associated with expression of GLUT1 (P < .05). In hypoxia, proliferation, invasion, resistance to apoptosis, and glycolysis of both Hela and Siha were enhanced compared with cells in normoxia (P < .05). Both gene and protein expressions of GLUT1 and hexokinase II were strengthened, whereas only the protein expression of HIF-1α was stronger in hypoxia than that in normoxia (P < .05). The results of Hela in normoxia and in hypoxia were similar to those of Siha (P > .05). HIF-1α plays a key role in cervical cancer both in vivo and in vitro. The role of HIF-1α can be implemented mainly by up-regulating its downstream gene, such as GLUT1, and the main mechanism may enhance glycolytic ability. Strong up-regulation and the role of HIF-1α suggest that HIF-1α could be an important factor in the onset and progression of cervical cancer and could be an attractive therapeutic molecular target for that type of cancer.
本研究旨在探讨低氧诱导因子-1（HIF-1）在糖酵解活性中的作用及其与宫颈癌恶性生物学行为的关系。采用免疫组织化学方法检测 158 例宫颈组织中 HIF-1α和葡萄糖转运蛋白 1（GLUT1）的蛋白表达和分布，其中正常宫颈上皮 28 例，宫颈上皮内瘤变 32 例，浸润性宫颈癌 98 例。用氯化钴诱导 Hela 和 Siha 细胞缺氧；通过比色法、Transwell、流式细胞术和酶联免疫吸附试验监测正常和缺氧环境下培养的细胞的生物学行为；免疫细胞化学、Western blot 和逆转录-聚合酶链反应观察正常和缺氧条件下细胞系中 HIF-1α、GLUT1 和己糖激酶Ⅱ的基因和蛋白表达。HIF-1α和 GLUT1 的表达从正常宫颈组织逐渐增加到宫颈上皮内瘤变，然后到宫颈癌。这些组之间存在显著差异（P<0.05）。HIF-1α与病理分化、临床分期、病变程度和患者年龄密切相关，而 GLUT1 与淋巴转移相关（P<0.05）。HIF-1α与 GLUT1 的表达密切相关（P<0.05）。缺氧时，Hela 和 Siha 细胞的增殖、侵袭、抗凋亡和糖酵解能力均强于常氧时（P<0.05）。GLUT1 和己糖激酶Ⅱ的基因和蛋白表达均增强，而缺氧时 HIF-1α的蛋白表达强于常氧时（P<0.05）。常氧和缺氧时 Hela 的结果与 Siha 相似（P>0.05）。HIF-1α在体内和体外均在宫颈癌中发挥关键作用。HIF-1α的作用主要通过上调其下游基因如 GLUT1 来实现，其主要机制可能是增强糖酵解能力。HIF-1α的强上调及其作用表明，HIF-1α可能是宫颈癌发病和进展的重要因素，可能成为该型癌症有吸引力的治疗分子靶点。
