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miR-326 reverses chemoresistance in human lung adenocarcinoma cells by targeting specificity protein 1

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Tumor Biology

Abstract

Cisplatin resistance is a major obstacle in the treatment of lung adenocarcinoma (LAD), and its mechanism has not been fully elucidated. Here, we report that miR-326 is downregulated in cisplatin-resistant A549/CDDP cells compared with parental A549 cells. Overexpression of miR-326 reversed cisplatin chemoresistance of LAD cells in vitro and in vivo. Moreover, we identified the specificity protein 1 (SP1) gene as a novel direct target of miR-326. Knockdown of SP1 revealed similar effects as that of ectopic miR-326 expression. Decreased miR-326 expression was also detected in tumor tissues sampled from LAD patients treated with cisplatin-based chemotherapy and was proved to be correlated with high expression of SP1 and decreased sensitivity to cisplatin. Furthermore, we show that the long noncoding RNA HOTAIR repression reverses chemoresistance of LAD cells partially through modulation of miR-326/SP1 pathway. In summary, we unveil a branch of the HOTAIR/miR-326/SP1 pathway that regulates chemoresistance of LAD cells.

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References

  1. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60:277–300.

    Article  PubMed  Google Scholar 

  2. Shen J, Stass SA, Jiang F. MicroRNAs as potential biomarkers in human solid tumors. Cancer Lett. 2013;329(2):125–36.

    Article  CAS  PubMed  Google Scholar 

  3. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism and function. Cell. 2004;116(2):281–97.

    Article  CAS  PubMed  Google Scholar 

  4. Zhou C, Chen Z, Dong J, Li J, Shi X, et al. Combination of serum miRNAs with Cyfra21-1 for the diagnosis of non-small cell lung cancer. Cancer let. 2015;367(2):138–46.

    Article  CAS  Google Scholar 

  5. Fang B, Wang R, Song HZ, Chen LB. microRNA-200b reverses chemoresistance of docetaxel-resistant human lung adenocarcinoma cells by targeting E2F3. Cancer. 2012;118(13):3365–76.

    Article  Google Scholar 

  6. Chen X, Jiang Y, Huang Z, Li D, Chen X, et al. miR-378 reverses chemoresistance to cisplatin in lung adenocarcinoma cells by targeting secreted clusterin. Sci Rep. 2016;6:19455.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Li J, Wang YP, Song YL, Fu ZM, et al. miR-27a regulates cisplatin resistance and metastasis by targeting RKIP in human lung adenocarcinoma cells. Mol Cancer. 2014;13:193.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Bitarte N, Bandres E, Boni V, Zarate R, Rodriguez J, et al. MicroRNA-451 is involved in the self-renewal, tumorigenicity, and chemoresistance of colorectal cancer stem cells. Stem Cells. 2011;29(11):1661–71.

    Article  CAS  PubMed  Google Scholar 

  9. Iliopoulos D, Lindahl-Allen M, Polytarchou C, Hirsch HA, Tsichlis PN, Struhl K. Loss of miR-200 inhibition of Suz12 leads to polycomb-mediated repression required for the formation and maintenance of cancer stem cells. Mol Cell. 2010;39(5):761–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ke J, Yao YL, Zhang J, Wang P, et al. Knockdown of long non-coding RNA HOTAIR inhibits malignant biological behaviors of human glioma cells via modulation of miR-326. Oncotarget. 2015;6(26):21934–49.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Das S, Kumar M, Negi V, Pattnaik B, et al. MicroRNA-326 regulates profibrotic functions of transforming growth factor-beta in pulmonary fibrosis. Am J Respir Cell Mol Biol. 2014;50:882–92.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Wu L, Hui H, Wang LJ, Wang H, Liu QF, Han SX. MicroRNA-326 functions as a tumor suppressor in colorectal cancer by targeting the nin one binding protein. Oncol Rep. 2015;33:2309–18.

    CAS  PubMed  Google Scholar 

  13. Liang Z, Wu H, Xia J, Li Y, et al. Involvement of miR- 326 in chemotherapy resistance of breast cancer through modulating expression of multidrug resistance-associated protein 1. Biochem Pharmacol. 2010;79:817–24.

    Article  CAS  PubMed  Google Scholar 

  14. Zhou J, Xu T, Yan Y, Qin R, et al. MicroRNA-326 functions as a tumor suppressor in glioma by targeting the Nin one binding protein (NOB1). PLoS One. 2013;8:e68469.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Sun C, Huang C, Li S, Yang C, et al. Has-miR-326 targets CCND1 and inhibits non-small cell lung cancer development. Oncotarget. 2016;7(7):8341–59. doi:10.18632/oncotarget.7071.

    PubMed  PubMed Central  Google Scholar 

  16. Cai M, Wang Z, Zhang J, Zhou H, Jin L, Bai R, et al. Adam17, a target of Mir-326, promotes Emt-induced cells invasion in lung adenocarcinoma. Cell Physiol Biochem. 2015;36:1175–85.

    Article  CAS  PubMed  Google Scholar 

  17. Fischer KR, Durrans A, Lee S, Sheng J, Li F, et al. Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature. 2015;527(7579):472–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Sun L, Yao Y, Liu B, Lin L, Yang M, et al. miR-200b and miR-15b regulate chemotherapy-induced epithelial mesenchymal transition in human tonge cancer cells by targeting BMI1. Oncogene. 2012;31:432–45.

    Article  CAS  PubMed  Google Scholar 

  19. Vizcaíno C, Mansilla S, Portugal J. Sp1 transcription factor: a long-standing target in cancer chemotherapy. Pharmacol Ther. 2015;152:111–24.

    Article  PubMed  Google Scholar 

  20. Safe S, Imanirad P, Sreevalsan S, Nair V, Jutooru I. Transcription factor Sp1, also known as specificity protein 1 as a therapeutic target. Expert Opin Ther Targets. 2014;18(7):759–69.

    Article  CAS  PubMed  Google Scholar 

  21. Guan H, Cai J, Zhang N, Wu J, et al. Sp1 is upregulated in human glioma, promotes MMP-2-mediated cell invasion and predicts poor clinical outcome. Int J Cancer. 2012;130(3):593–601.

    Article  CAS  PubMed  Google Scholar 

  22. Bretones G, Delgado MD, León J. Myc and cell cycle control. Biochim Biophys Acta. 2015;1849(5):506–16.

    Article  CAS  PubMed  Google Scholar 

  23. Bedolla RG, Gong J, Prihoda TJ, Yeh IT, et al. Predictive value of Sp1/Sp3/FLIP signature for prostate cancer recurrence. PLoS One. 2012;7:e44917.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Wang L, Wei D, Huang S, Peng Z, et al. Transcription factor Sp1 expression is a significant predictor of survival in human gastric cancer. Clin Cancer Res. 2003;9(17):6371–80.

    CAS  PubMed  Google Scholar 

  25. Hsu TI, Wang MC, Chen SY, Yeh YM, Su WC, Chang WC, et al. Sp1 expression regulates lung tumor progression. Oncogene. 2012;31:3973–88.

    Article  CAS  PubMed  Google Scholar 

  26. Lou Z, O’Reilly S, Liang H, Maher VM, et al. Down-regulation of overexpressed sp1 protein in human fibrosarcoma cell lines inhibits tumor formation. Cancer Res. 2005;65:1007–17.

    CAS  PubMed  Google Scholar 

  27. Li L, Gao P, Li Y, Shen Y, Xie J, et al. JMJD2A-dependent silencing of Sp1 in advanced breast cancer promotes metastasis by downregulation of DIRAS3. Breast Cancer Res Treat. 2014;147(3):487–500.

    Article  CAS  PubMed  Google Scholar 

  28. Zhang A, Zhao JC, Kim J, Fong KW, et al. LncRNA HOTAIR enhances the androgen-receptor-mediated transcriptional program and drives castration-resistant prostate cancer. Cell Rep. 2015;13(1):209–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. He Y, Meng XM, Huang C, Wu BM, et al. Long noncoding RNAs: novel insights into hepatocelluar carcinoma. Cancer Lett. 2014;344(1):20–7.

    Article  CAS  PubMed  Google Scholar 

  30. Bhan A, Mandal SS. LncRNA HOTAIR: a master regulator of chromatin dynamics and cancer. Biochim Biophys Acta. 2015;1856(1):151–64.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported by Zhejiang Provincial Natural Science Foundation of China (Grant No. LY14H160002) and Zhejiang Provincial Medicine and Health Science Research Foundation of China (Grant No. 2014KYB248).

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Authors and Affiliations

  1. Department of Central Laboratory, Yinzhou People’s Hospital, Ningbo, 315040, China

    Jipeng Li, Shanfeng Li, Zhe Chen, Jianhua Wang, Ying Chen, Mingwei Jin & Wanjun Yu

  2. Department of Medical Oncology, Yinzhou People’s Hospital, Ningbo, 315040, China

    Zhengyang Xu

  3. Department of Respiratory and Critical Care Medicine, Yinzhou People’s Hospital, 251 East Baizhang Road, Ningbo, 315040, China

    Wanjun Yu

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  1. Jipeng Li
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  2. Shanfeng Li
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Correspondence to Wanjun Yu.

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Table S1

Primers for plasmid construction. (DOC 33 kb)

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Li, J., Li, S., Chen, Z. et al. miR-326 reverses chemoresistance in human lung adenocarcinoma cells by targeting specificity protein 1. Tumor Biol. 37, 13287–13294 (2016). https://doi.org/10.1007/s13277-016-5244-2

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  • DOI: https://doi.org/10.1007/s13277-016-5244-2

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