The effects and mechanisms of SLC34A2 in tumorigenesis and progression of human non-small cell lung cancer

Journal of Biomedical Science

Wen Zhu¹  Lunxu Liu²  Xuechao Zhang¹  Guoxing Zhong¹  Zhixing Cao¹  Jiang Ren¹  Qingping Ma¹  Sujuan Ye¹  Yan Yang¹  Qiang Pu²  Weihan Yang¹  Yu Wang¹ 

[1] 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, Chengdu, 610041, Sichuan, P. R. China;Department of Thoracic Surgery, West China Hospital, Sichuan University, No. 37 Guo Xue Xiang, Chengdu, 610041, Sichuan, P. R. China

关键词: Mechanism;    Tumorigenesis and progression;    NSCLC;    ATII cells;    SLC34A2;   

Others  :  1219618
DOI  :  10.1186/s12929-015-0158-7

 received in 2014-10-10, accepted in 2015-06-18,  发布年份 2015

【 摘 要 】

Background

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.

Results

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.

Conclusions

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.

【 授权许可】

   
2015 Wang et al.

【 图 表 】

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【 参考文献 】

• [1]Herbst RSHJ, Lippman SM. Lung cancer. N Engl J Med. 2008; 359:1367-1380.
• [2]Feild JA, Zhang L, Brun KA, Brooks DP, Edwards RM. Cloning and functional characterization of a sodium-dependent phosphate transporter expressed in human lung and small intestine. Biochem Biophys Res Commun. 1999; 258:578-582.
• [3]Xu H, Bai L, Collins JF, Ghishan FK. Molecular cloning, functional characterization, tissue distribution, and chromosomal localization of a human, small intestinal sodium-phosphate (Na + −Pi) transporter (SLC34A2). Genomics. 1999; 62:281-284.
• [4]Yin BWT, Kiyamova R, Chua R, Caballero OL, Gout I, Gryshkova V et al.. Monoclonal antibody MX35 detects the membrane transporter NaPi2b (SLC34A2) in human carcinomas. Cancer Immun. 2008; 8:1-9.
• [5]Hashimoto M, Wang DY, Kamo T, Zhu Y, Tsujiuchi T, Konishi Y et al.. Isolation and localization of type IIb Na/Pi cotransporter in the developing rat lung. Am J Pathol. 2000; 157:21-27.
• [6]Traebert M, Hattenhauer O, Murer H, Kaissling B, Biber J. Expression of type II Na-picotransporter in alveolar type II cells. Am J Physiol Lung Cell Mol Physiol. 1999; 277:868-873.
• [7]Corut A, Senyigit A, Ugur SA, Altin S, Ozcelik U, Calisir H et al.. Mutations in SLC34A2 cause pulmonary alveolar microlithiasis and are possibly associated with testicular microlithiasis. Am J Hum Genet. 2006; 79:650-656.
• [8]Cerri MF, de Rezende LCD, Paes MF, Silva IV, Rangel LBA. The cotransporter NaPi-IIb: characteristics, regulation and its role in carcinogenesis. Applied Cancer Research. 2010; 30:197-203.
• [9]Kopantzev EP, Monastyrskaya GS, Vinogradova TV, Zinovyeva MV, Kostina MB, Filyukova OB et al.. Differences in gene expression levels between early and later stages of human lung development are opposite to those between normal lung tissue and non-small lung cell carcinoma. Lung Cancer. 2008; 62:23-34.
• [10]Shibasaki Y, Etoh N, Hayasaka M, Takahashi M, Kakitani M, Yamashita T et al.. Targeted deletion of the tybe IIb Na( + )−dependent Pi-co-transporter, NaPi-IIb, results in early embryonic lethality. Biochem Biophys Res Commun. 2009; 381:482-486.
• [11]Monk M, Holding C. Human embryonic genes re-expressed in cancer cells. Oncogene. 2001; 20:8085-8091.
• [12]Dreesen O, Brivanlou AH. Signaling pathways in cancer and embryonic stem cells. Stem Cell Rev Rep. 2007; 3:7-17.
• [13]Chen CM, Behringer RR. Ovca1 regulates cell proliferation, embryonic development, and tumorigenesis. Genes Dev. 2004; 18:320-332.
• [14]Uhal BD. Cell cycle kinetics in the alveolar epithelium. Am J Physiol Lung Cell Mol Physiol. 1997; 272:L1031-L1045.
• [15]Singh G, Katyal SL, Torikata C. Carcinoma of type II pneumocytes: immunodiagnosis of a subtype of “bronchioloalveolar carcinomas”. Am J Pathol. 1981;102:195–208.
• [16]Kitinya JN, Sueishi K, Tanaka K, Katsuda Y. Immunoreactivity of surfactant-apoprotein in adenocarcinomas, large cell and small cell carcinomas of the lung. Acta Pathol Jpn. 1986;36:1271–8.
• [17]Gazdar AF, Linnoila RI, Kurita Y, Oie HK, Mulshine JL, Clark JC, et al. Peripheral airway cell differentiation in human lung cancer cell lines. Cancer Res. 1990;50:5481–7.
• [18]Yang W, Wang Y, Pu Q, Ye S, Ma Q, Ren J et al.. Elevated expression of SLC34A2 inhibits the viability and invasion of A549 cells. Mol Med Rep. 2014; 10:1205-1214.
• [19]Strizzi L, Bianco C, Normanno N, Salomon D. Cripto-1: a multifunctional modulator during embryogenesis and oncogenesis. Oncogene. 2005; 24:5731-5741.
• [20]Liu H, Kho AT, Kohane IS, Sun Y. Predicting survival within the lung cancer histopathological hierarchy using a multi-scale genomic model of development. PLoS Med. 2006; 3:e232.
• [21]Williams TM, Lisanti MP. Caveolin-1 in oncogenic transformation, cancer, and metastasis. Am J Physiol Cell Physiol. 2005; 288:C494-C506.
• [22]Bélanger MM, Gaudreau M, Roussel É, Couet J. Research paper role of caveolin-1 in etoposide resistance development in A549 lung cancer cells. Cancer Biol Ther. 2004; 3:954-959.
• [23]Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001; 414:105-111.
• [24]Kinnard WV, Tuder R, Papst P, Fisher JH. Regulation of alveolar type II cell differentiation and proliferation in adult rat lung explants. Am J Respir Cell Mol Biol. 1994; 11:416-425.
• [25]Thaete LG, Malkinson AM. Cells of origin of primary pulmonary neoplasms in mice: morphologic and histochemical studies. Exp Lung Res. 1991; 17:219-228.
• [26]Smith B. Cell line A549: a model system for the study of alveolar type II cell function. Am Rev Respir Dis. 1977; 115:285-293.
• [27]McDowell E, McLaughlin J, Merenyl D, Kieffer R, Harris C, Trump B. The respiratory epithelium. V. Histogenesis of lung carcinomas in the human. J Natl Cancer Inst. 1978; 61:587.
• [28]Linnoila R, Mulshine J, Steinberg S, Gazdar A. Expression of surfactant-associated protein in non-small-cell lung cancer: a discriminant between biologic subsets. J Natl Cancer Inst Monogr. 1992;16:61–66.
• [29]Tsutahara S, Shijubo N, Hirasawa M, Honda Y, Satoh M, Kuroki Y et al.. Lung adenocarcinoma with type II pneumocyte characteristics. Eur Respir J. 1993; 6:135-137.
• [30]Ten Have-Opbroek A, Benfield J, Van Krieken J, Dijkman J. The alveolar type II cell is a pluripotential stem cell in the genesis of human adenocarcinomas and squamous cell carcinomas. Histol Histopathol. 1997; 12:319-336.
• [31]Chang SH, Yu KN, Lee YS, An GH, Beck GR, Colburn NH et al.. Elevated inorganic phosphate stimulates Akt-ERK1/2-Mnk1 signaling in human lung cells. Am J Respir Cell Mol Biol. 2006; 35:528-539.
• [32]Jin H, Chang SH, Xu CX, Shin JY, Chung YS, Park SJ et al.. High dietary inorganic phosphate affects lung through altering protein translation, cell cycle, and angiogenesis in developing mice. Toxicol Sci. 2007; 100:215-223.
• [33]Xu CX, Jin H, Chung YS, Shin JY, Hwang SK, Kwon JT, et al. Low dietary inorganic phosphate affects the lung growth of developing mice. J Vet Sci. 2009;10:105–1.
• [34]Jin H, Xu CX, Lim HT, Park SJ, Shin JY, Chung YS, et al. High dietary inorganic phosphate increases lung tumorigenesis and alters Akt signaling. Am J Respir Crit Care Med. 2009;179:59–68.
• [35]Xu CX, Jin H, Lim HT, Ha YC, Chae CH, An GH et al.. Low dietary inorganic phosphate stimulates lung tumorigenesis through altering protein translation and cell cycle in K-ras LA1 mice. Nutr Cancer. 2010; 62:525-532.
• [36]Testa JR, Bellacosa A. AKT plays a central role in tumorigenesis. Sci STKE. 2001; 98:11598-11603.
• [37]Hay N. The Akt-mTOR tango and its relevance to cancer. Cancer Cell. 2005; 8:179-183.
• [38]Zhang D, Brodt P. Type 1 insulin-like growth factor regulates MT1-MMP synthesis and tumor invasion via PI 3-kinase/Akt signaling. Oncogene. 2003; 22:974-982.
• [39]Qian Y, Corum L, Meng Q, Blenis J, Zheng JZ, Shi X et al.. PI3K induced actin filament remodeling through Akt and p70S6K1: implication of essential role in cell migration. Am J Physiol Cell Physiol. 2004; 286:C153-C163.
• [40]Roberts P, Der C. Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene. 2007; 26:3291-3310.