Transketolase is upregulated in metastatic peritoneal implants and promotes ovarian cancer cell proliferation
Transketolase is upregulated in metastatic peritoneal implants and promotes ovarian cancer cell proliferation
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DOI：
10.1007/s10585-015-9718-1
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发表时间：
2015-06-01
影响因子：
4
通讯作者：
Oehler, Martin K.
中科院分区：
文献类型：
--
作者：
Ricciardelli, Carmela;Lokman, Noor A.;Oehler, Martin K.
卵巢癌是最致命的妇科癌症，其特征在于上皮细胞从卵巢表面脱落，随后转移并植入到腹部器官的腹膜表面上。我们的蛋白质组学研究调查腹膜（LP-9）和卵巢癌（OVCAR-5）细胞之间的相互作用，发现转酮醇酶（TKT）在共培养系统中受到调节。本研究通过免疫组化表征了晚期（III/IV期）浆液性卵巢癌（n = 125例原发性和n = 54例腹膜转移）、正常卵巢（n = 6）和良性浆液性囊腺瘤（n = 10）中TKT的表达。此外，我们还在体外研究了TKT在卵巢癌细胞中的作用。核TKT存在于检查的所有原发性浆液性卵巢癌组织中（中位数82.0%，范围16.5- 100%），并且与匹配的原发性癌症相比，腹膜转移中的核TKT显著增加（P = 0.01，Wilcoxon秩检验）。Kaplan-Meier生存率和考克斯回归分析显示，腹膜转移瘤中高核TKT阳性率（> 94%）与总生存率降低（P = 0.006）和卵巢癌死亡风险增加2.8倍（95% CI 1.29-5.90，P = 0.009）显著相关。通过siRNA敲低TKT显著降低SKOV-3细胞增殖，但对其运动性或侵袭性没有影响。TKT活性的抑制剂羟硫胺显著抑制四种卵巢癌细胞系（OV-90、SKOV-3、OVCAR-3和OVCAR-5）和从患者腹水中分离的原代浆液性卵巢癌细胞的增殖。总之，这些发现表明TKT在转移性卵巢癌细胞的增殖中起重要作用，并可用作晚期疾病的新的治疗靶点。
Ovarian cancer, the most lethal gynaecological cancer, is characterised by the shedding of epithelial cells from the ovarian surface, followed by metastasis and implantation onto the peritoneal surfaces of abdominal organs. Our proteomic studies investigating the interactions between peritoneal (LP-9) and ovarian cancer (OVCAR-5) cells found transketolase (TKT) to be regulated in the co-culture system. This study characterized TKT expression in advanced stage (III/IV) serous ovarian cancers (n = 125 primary and n = 54 peritoneal metastases), normal ovaries (n = 6) and benign serous cystadenomas (n = 10) by immunohistochemistry. In addition, we also evaluated the function of TKT in ovarian cancer cells in vitro. Nuclear TKT was present in all primary serous ovarian cancer tissues examined (median 82.0 %, range 16.5-100 %) and was significantly increased in peritoneal metastases compared with matching primary cancers (P = 0.01, Wilcoxon Rank test). Kaplan-Meier survival and Cox regression analyses showed that high nuclear TKT positivity in peritoneal metastases (> 94 %) was significantly associated with reduced overall survival (P = 0.006) and a 2.8 fold increased risk of ovarian cancer death (95 % CI 1.29-5.90, P = 0.009). Knockdown of TKT by siRNAs significantly reduced SKOV-3 cell proliferation but had no effect on their motility or invasion. Oxythiamine, an inhibitor of TKT activity, significantly inhibited the proliferation of four ovarian cancer cell lines (OV-90, SKOV-3, OVCAR-3 and OVCAR-5) and primary serous ovarian cancer cells isolated from patient ascites. In conclusion, these findings indicate that TKT plays an important role in the proliferation of metastatic ovarian cancer cells and could be used as novel therapeutic target for advanced disease.