Wang Yu, Yang Weihan, Pu Qiang, Yang Yan, Ye Sujuan, Ma Qingping, Ren Jiang, Cao Zhixing, Zhong Guoxing, Zhang Xuechao, Liu Lunxu, Zhu Wen
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, NO. 1, Keyuan 4th Road, Gaopeng Street, High Technological Development Zone, 610041, Chengdu, Sichuan, P. R. China.
Department of Thoracic Surgery, West China Hospital, Sichuan University, No. 37 Guo Xue Xiang, 610041, Chengdu, Sichuan, P. R. China.
J Biomed Sci. 2015 Jul 9;22(1):52. doi: 10.1186/s12929-015-0158-7.
SLC34A2 with highest expressions in lung, small intestine and kidney encoded a type 2b sodium-dependent phosphate transporter (NaPi-IIb). In lung, SLC34A2 only expressed in the apical membrane of type II alveolar epithelium cells (ATII cells) and played a pivotal role during the fetal lung development and embryonic development. ATII cells acting as multifunctional stem cells might transform into NSCLC after undergoing exogenous or endogenous factors. Increasing evidences showed that the genes performing critical roles during embryogenesis were also expressed during the development of cancer. In addition, recent research found the expression of SLC34A2 had a significant difference between the surgical samples of NSCLC and normal tissues, and SLC34A2 was down-regulated in lung adenocarcinoma cell line A549 and up-regulation expression of SLC34A2 could significantly inhibit cell viability and invasion of A549 in vitro. These results suggested SLC34A2 might play an important role in the development of NSCLC. However, the role of SLC34A2 in tumorigenesis and progression of NSCLC remains unknown.
Our study found that SLC34A2 was also significantly down-regulated in 14/15 of examined NSCLC tissues. Moreover, we found that expressions of SLC34A2 were reduced in six NSCLC cell lines for the first time. Our result also revealed a dramatic inhibitory effects of SLC34A2 on cell growth, migration and invasion of several NSCLC cell lines. SLC34A2 also strongly inhibited tumor growth and metastasis ability in A549 subcutaneous tumor model and lung metastasis model, respectively. Further studies found that the suppressive effects of SLC34A2 on tumorigenesis and progression might be associated with the down-regulation of related protein in PI3K/Akt and Ras/Raf/MEK signal pathway.
For the first time, our data indicated that SLC34A2 could exert significantly suppressive effects on tumorigenesis and progression of NSCLC. SLC34A2 might provide new insights for further understanding the early pathogenesis of human NSCLC.
SLC34A2在肺、小肠和肾脏中表达最高，编码一种2b型钠依赖性磷酸盐转运体（NaPi-IIb）。在肺中，SLC34A2仅在II型肺泡上皮细胞（ATII细胞）的顶端膜表达，在胎儿肺发育和胚胎发育过程中起关键作用。ATII细胞作为多功能干细胞，在外源性或内源性因素作用下可能转化为非小细胞肺癌（NSCLC）。越来越多的证据表明，在胚胎发生过程中起关键作用的基因在癌症发展过程中也有表达。此外，最近的研究发现，NSCLC手术样本与正常组织中SLC34A2的表达存在显著差异，SLC34A2在肺腺癌细胞系A549中表达下调，上调SLC34A2的表达可显著抑制A549细胞在体外的活力和侵袭能力。这些结果提示SLC34A2可能在NSCLC的发展中起重要作用。然而，SLC34A2在NSCLC肿瘤发生和进展中的作用仍不清楚。
我们的研究发现，在15例检测的NSCLC组织中有14例SLC34A2也显著下调。此外，我们首次发现6种NSCLC细胞系中SLC34A2的表达降低。我们的结果还揭示了SLC34A2对几种NSCLC细胞系的细胞生长、迁移和侵袭具有显著的抑制作用。SLC34A2在A549皮下肿瘤模型和肺转移模型中也分别强烈抑制肿瘤生长和转移能力。进一步研究发现，SLC34A2对肿瘤发生和进展的抑制作用可能与PI3K/Akt和Ras/Raf/MEK信号通路中相关蛋白的下调有关。
我们的数据首次表明，SLC34A2可对NSCLC的肿瘤发生和进展产生显著抑制作用。SLC34A2可能为进一步了解人类NSCLC的早期发病机制提供新的见解。
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