Department of Biophysics, School of Physics Science, Nankai University, Tianjin, China.
PLoS One. 2013 Aug 5;8(8):e70550. doi: 10.1371/journal.pone.0070550. Print 2013.
Solid tumors exist in a hypoxic microenvironment, and possess high-glycolytic metabolites. To avoid the acidosis, tumor cells must exhibit a dynamic cytosolic pH regulation mechanism(s). The voltage-gated proton channel Hv1 mediates NADPH oxidase function by compensating cellular loss of electrons with protons. Here, we showed for the first time, that Hv1 expression is increased in colorectal tumor tissues and cell lines, associated with poor prognosis. Immunohistochemistry showed that Hv1 is strongly expressed in adenocarcinomas but not or lowly expressed in normal colorectal or hyperplastic polyps. Hv1 expression in colorectal cancer is significantly associated with the tumor size, tumor classification, lymph node status, clinical stage and p53 status. High Hv1 expression is associated significantly with shorter overall and recurrence-free survival. Furthermore, real-time RT-PCR and immunocytochemistry showed that Hv1 is highly expressed in colorectal cancer cell lines, SW620, HT29, LS174T and Colo205, but not in SW480. Inhibitions of Hv1 expression and activity in the highly metastatic SW620 cells by small interfering RNA (siRNA) and Zn(2+) respectively, markedly decrease the cell invasion and migration, restraint proton extrusion and the intracellular pH recovery. Our results suggest that Hv1 may be used as a potential biomarker for diagnosis and prognosis of colorectal carcinoma, and a potential target for anticancer drugs in colorectal cancer therapy.
实体瘤存在于缺氧的微环境中，具有高糖酵解代谢物。为了避免酸中毒，肿瘤细胞必须表现出动态的细胞质 pH 调节机制。电压门控质子通道 Hv1 通过用质子补偿细胞电子的损失来介导 NADPH 氧化酶的功能。在这里，我们首次表明，Hv1 在结直肠肿瘤组织和细胞系中表达增加，与预后不良相关。免疫组织化学显示，Hv1 在腺癌中强烈表达，但在正常结直肠或增生性息肉中不表达或低表达。在结直肠癌中，Hv1 的表达与肿瘤大小、肿瘤分类、淋巴结状态、临床分期和 p53 状态显著相关。高 Hv1 表达与总生存期和无复发生存期明显缩短相关。此外，实时 RT-PCR 和免疫细胞化学显示，Hv1 在结直肠癌细胞系 SW620、HT29、LS174T 和 Colo205 中高度表达，但在 SW480 中不表达。用小干扰 RNA (siRNA) 和 Zn(2+) 分别抑制高转移性 SW620 细胞中的 Hv1 表达和活性，显著降低了细胞侵袭和迁移、抑制质子外排和细胞内 pH 恢复。我们的结果表明，Hv1 可作为结直肠癌诊断和预后的潜在标志物，也是结直肠癌治疗中抗癌药物的潜在靶点。
