Int J Oncol：阻断缺氧调控的TMPRSS4治疗肿瘤

早期研究证实TMPRSS4的过度表达与胰腺癌、大肠癌和甲状腺癌等类型癌症的发生发展有关。TMPRSS4是一种细胞表面跨膜丝氨酸蛋白酶，这一蛋白的表达对肿瘤细胞的迁移和转移有作用。

过去，有几项研究探讨了TMPRSS4基因表达水平以及蛋白产物。最近刊登在Int J Oncol杂志上的一则研究中，研究人员用定量RT-PCR和蛋白质染色来评估原发性非小细胞肺癌（NSCLC）组织和肺肿瘤细胞株中TMPRSS4的表达情况。

结果发现在转录水平上，正常肺组织相比，大多数人类鳞状细胞癌和腺癌组织中TMPRSS4都显着升高。研究人员收集了超过100例非小细胞肺癌原发肿瘤和正常标本，用兔抗-TMPRSS4抗体染色证实在鳞状细胞癌和腺癌组织中起蛋白表达水平较高，而在正常肺组织中很少或根本没有染色的蛋白表达。

在体外研究中，人源不同肺肿瘤细胞株表达TMPRSS4蛋白的水平式不一样的。有趣的是，TMPRSS4 mRNA表达水平高的肿瘤细胞株用免疫染色或流式细胞仪检测时，却检测不到其蛋白表达。

然而，肿瘤细胞在缺氧环境下培养时，TMPRSS4蛋白表达上调。这一结果证实体内缺氧可能上调TMPRSS4蛋白表达。总的来说，这些结果表明，在非小细胞肺癌中TMPRSS4蛋白过度表达，可能是一种潜在的治疗靶点。

doi:10.3892/ijo.2012.1513
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Expression of TMPRSS4 in non-small cell lung cancer and its modulation by hypoxia.

Nguyen TH, Weber W, Havari E, Connors T, Bagley RG, McLaren R, Nambiar PR, Madden SL, Teicher BA, Roberts B, Kaplan J, Shankara S.

Overexpression of TMPRSS4, a cell surface-associated transmembrane serine protease, has been reported in pancreatic, colorectal and thyroid cancers, and has been implicated in tumor cell migration and metastasis. Few reports have investigated both TMPRSS4 gene expression levels and the protein products. In this study, quantitative RT-PCR and protein staining were used to assess TMPRSS4 expression in primary non-small cell lung carcinoma (NSCLC) tissues and in lung tumor cell lines. At the transcriptional level, TMPRSS4 message was significantly elevated in the majority of human squamous cell and adenocarcinomas compared with normal lung tissues. Staining of over 100 NSCLC primary tumor and normal specimens with rabbit polyclonal anti-TMPRSS4 antibodies confirmed expression at the protein level in both squamous cell and adenocarcinomas with little or no staining in normal lung tissues. Human lung tumor cell lines expressed varying levels of TMPRSS4 mRNA in vitro. Interestingly, tumor cell lines with high levels of TMPRSS4 mRNA failed to show detectable TMPRSS4 protein by either immunoblotting or flow cytometry. However, protein levels were increased under hypoxic culture conditions suggesting that hypoxia within the tumor microenvironment may upregulate TMPRSS4 protein expression in vivo. This was supported by the observation of TMPRSS4 protein in xenograft tumors derived from the cell lines. In addition, staining of human squamous cell carcinoma samples for carbonic anhydrase IX (CAIX), a hypoxia marker, showed TMPRSS4 positive cells adjacent to CAIX positive cells. Overall, these results indicate that the cancer-associated TMPRSS4 protein is overexpressed in NSCLC and may represent a potential therapeutic target.