Song Taejong, Jeon Hye-Kyung, Hong Ji Eun, Choi Jung-Joo, Kim Tae-Joong, Choi Chel Hun, Bae Duk-Soo, Kim Byoung-Gie, Lee Jeong-Won
Department of Obstetrics and Gynecology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.
Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Cancer Res Treat. 2017 Jul;49(3):595-606. doi: 10.4143/crt.2016.034. Epub 2016 Sep 27.
This study was conducted to investigate whether a proton pump inhibitor (PPI) could enhance chemosensitivity via the inhibition of vacuolar-type H ATPase (V-ATPase) in cervical cancer.
The expression of V-ATPase was evaluated in 351 formalin-fixed, paraffin-embedded human cervical cancer tissues using immunohistochemistry and compared with clinicopathologic risk factors for disease prognosis. The influence of cell proliferation and apoptosis following V-ATPase siRNA transfection or esomeprazole pretreatment was assessed in cervical cancer cell lines using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide and enzyme-linked immunosorbent assay, respectively.
Immunohistochemical analysis revealed that V-ATPase was expressed in about 60% of cervical cancer tissue samples (211/351), and the expression was predominantly found in adenocarcinoma histology (p=0.016). Among patients with initially bulky cervical cancer (n=89), those with V-ATPase expression had shorter disease-free survival (p=0.005) and overall survival (p=0.023). Co-treatment with V-ATPase siRNA or esomeprazole with paclitaxel significantly decreased the cell proliferation of cervical cancer cell lines, including HeLa and INT407, compared to cell lines treated with paclitaxel alone (p < 0.01). Moreover, V-ATPase siRNA or esomeprazole followed by paclitaxel significantly increased the expression of active caspase-3 in these cells compared to cells treated with paclitaxel alone (both, p < 0.05).
V-ATPase was predominantly expressed in cervical adenocarcinoma, and the expression of V-ATPases was associated with poor prognosis. The inhibition of V-ATPase via siRNA or PPI (esomeprazole) might enhance the chemosensitivity of paclitaxel in cervical cancer cells.
本研究旨在探讨质子泵抑制剂(PPI)是否可通过抑制宫颈癌中的液泡型H⁺-ATP酶(V-ATP酶)来增强化疗敏感性。
采用免疫组织化学方法评估351例福尔马林固定、石蜡包埋的人宫颈癌组织中V-ATP酶的表达,并与疾病预后的临床病理危险因素进行比较。分别使用3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐和酶联免疫吸附测定法,评估V-ATP酶小干扰RNA(siRNA)转染或埃索美拉唑预处理后对宫颈癌细胞系细胞增殖和凋亡的影响。
免疫组织化学分析显示,约60%的宫颈癌组织样本(211/351)表达V-ATP酶,且该表达主要见于腺癌组织学类型(p=0.016)。在初始为巨块型宫颈癌的患者(n=89)中,表达V-ATP酶的患者无病生存期(p=0.005)和总生存期(p=0.023)较短。与单独使用紫杉醇处理的细胞系相比,V-ATP酶siRNA或埃索美拉唑与紫杉醇联合处理显著降低了宫颈癌细胞系(包括HeLa和INT407)的细胞增殖(p<0.01)。此外,与单独使用紫杉醇处理的细胞相比,V-ATP酶siRNA或埃索美拉唑预处理后再使用紫杉醇显著增加了这些细胞中活化半胱天冬酶-3的表达(两者均p<0.05)。
V-ATP酶主要表达于宫颈腺癌中,其表达与预后不良相关。通过siRNA或PPI(埃索美拉唑)抑制V-ATP酶可能增强紫杉醇对宫颈癌细胞的化疗敏感性。