TBL1XR1 is involved in c-Met-mediated tumorigenesis of human nonsmall cell lung cancer

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Abstract

Nonsmall cell lung carcinoma (NSCLC) contributes to the highest number of cancer deaths globally. Metastases and chemoresistance are two major confounders to the treatment efficacy in NSCLC. Transducin (β)-like 1 X-linked receptor 1 (TBL1XR1) has been associated with high rates of metastases in breast, gastric, and stomach cancers. However, the role of TBL1XR1 in lung cancers remains underexplored. We selected matched and cancerous lung tissues to establish the upregulation of TBL1XR1. Using in vitro assays, we assessed the influence of TBL1XR1 on various cancer phenotypes, namely cell proliferation, chemoresistance, invasion, and metastases in a CRISPR-Cas9-mediated knock out model (A549 cells), and H460 cell lines overexpressing TBL1XR1. We found that TBL1XR1 is overexpressed in NSCLC tissue and patient sera in comparison to paired adjacent normal tissue. Overexpression of TBL1XR1 in NSCLC cell lines mediates cell survival, proliferation, and metastases. TBL1XR1 was found to regulate MEK and Akt pathways through their master regulator c-Met. We observed that activation of c-Met is downregulated in the absence of TBL1XR1. Our study strengthens the contention that TBL1XR1 is a biomarker for prognosis of NSCLC. It may also be considered as an adjunct or core therapeutic target to overcome cisplatin resistance in lung cancers.

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References

  1. 1.

    Liu Y, Liu G, Wu H, Jian W, Wild SH, Gasevic D. Sex differences in non-communicable disease prevalence in China: a cross-sectional analysis of the China Health and Retirement Longitudinal Study in 2011. BMJ Open. 2017;7:e017450.

  2. 2.

    Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.

  3. 3.

    Cao M, Chen W. Epidemiology of lung cancer in China. Thorac Cancer. 2019;10:3–7.

  4. 4.

    Berghmans T, Paesmans M, Sculier JP. Prognostic factors in stage III non-small cell lung cancer: a review of conventional, metabolic and new biological variables. Ther Adv Med Oncol. 2011;3:127–38.

  5. 5.

    Popper HH. Progression and metastasis of lung cancer. Cancer Metastas Rev. 2016;35:75–91.

  6. 6.

    Wang J, Wei Q, Wang X, Tang S, Liu H, Zhang F, et al. Transition to resistance: an unexpected role of the EMT in cancer chemoresistance. Genes Dis. 2016;3:3–6.

  7. 7.

    Liao LM, Zhang FH, Yao GJ, Ai SF, Zheng M, Huang L. Role of long noncoding RNA 799 in the metastasis of cervical cancer through upregulation of TBL1XR1 expression. Mol Ther Nucleic acids. 2018;13:580–9.

  8. 8.

    Budczies J, von Winterfeld M, Klauschen F, Bockmayr M, Lennerz JK, Denkert C, et al. The landscape of metastatic progression patterns across major human cancers. Oncotarget. 2015;6:570–83.

  9. 9.

    Liu L, Lin C, Liang W, Wu S, Liu A, Wu J, et al. TBL1XR1 promotes lymphangiogenesis and lymphatic metastasis in esophageal squamous cell carcinoma. Gut. 2015;64:26–36.

  10. 10.

    Liu F, He Y, Cao Q, Liu N, Zhang W. TBL1XR1 is highly expressed in gastric cancer and predicts poor prognosis. Dis Markers. 2016;2016:2436518.

  11. 11.

    Liu H, Xu Y, Zhang Q, Li K, Wang D, Li S, et al. Correlations between TBL1XR1 and recurrence of colorectal cancer. Sci Rep. 2017;7:44275.

  12. 12.

    Cao Q, Wang Z, Wang Y, Liu F, Dong Y, Zhang W, et al. TBL1XR1 promotes migration and invasion in osteosarcoma cells and is negatively regulated by miR-186-5p. Am J Cancer Res. 2018;8:2481–93.

  13. 13.

    Ostrom QT, Gittleman H, Fulop J, Liu M, Blanda R, Kromer C. et al. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2008–12. Neuro-Oncol. 2015;17(Suppl 4):iv1–62.

  14. 14.

    Liu F, Song S, Yi Z, Zhang M, Li J, Yang F, et al. HGF induces EMT in non-small-cell lung cancer through the hBVR pathway. Eur J Pharmacol. 2017;811:180–90.

  15. 15.

    Liu Y, Liu JH, Chai K, Tashiro S, Onodera S, Ikejima T. Inhibition of c-Met promoted apoptosis, autophagy and loss of the mitochondrial transmembrane potential in oridonin-induced A549 lung cancer cells. J Pharm Pharmacol. 2013;65:1622–42.

  16. 16.

    Sun CY, Zhu Y, Li XF, Wang XQ, Tang LP, Su ZQ, et al. Scutellarin increases cisplatin-induced apoptosis and autophagy to overcome cisplatin resistance in non-small cell lung cancer via ERK/p53 and c-met/AKT signaling pathways. Front Pharmacol. 2018;9:92.

  17. 17.

    Wang S, Han H, Hu Y, Yang W, Lv Y, Wang L, et al. MicroRNA-130a-3p suppresses cell migration and invasion by inhibition of TBL1XR1-mediated EMT in human gastric carcinoma. Mol Carcinog. 2018;57:383–92.

  18. 18.

    Gieseg MA, Man MZ, Gorski NA, Madore SJ, Kaldjian EP, Leopold WR. The influence of tumor size and environment on gene expression in commonly used human tumor lines. BMC Cancer. 2004;4:35.

  19. 19.

    Bell R, Barraclough R, Vasieva O. Gene expression meta-analysis of potential metastatic breast cancer markers. Curr Mol Med. 2017;17:200–10.

  20. 20.

    Riker AI, Enkemann SA, Fodstad O, Liu S, Ren S, Morris C, et al. The gene expression profiles of primary and metastatic melanoma yields a transition point of tumor progression and metastasis. BMC Med Genom. 2008;1:13.

  21. 21.

    Zhao Y, Lin H, Jiang J, Ge M, Liang X. TBL1XR1 as a potential therapeutic target that promotes epithelial-mesenchymal transition in lung squamous cell carcinoma. Exp Ther Med. 2019;17:91–8.

  22. 22.

    Abbas T, Dutta A. p21 in cancer: intricate networks and multiple activities. Nat Rev Cancer. 2009;9:400–14.

  23. 23.

    Maeda M, Johnson KR, Wheelock MJ. Cadherin switching: essential for behavioral but not morphological changes during an epithelium-to-mesenchyme transition. J Cell Sci. 2005;118:873–87.

  24. 24.

    Bae GY, Choi SJ, Lee JS, Jo J, Lee J, Kim J, et al. Loss of E-cadherin activates EGFR-MEK/ERK signaling, which promotes invasion via the ZEB1/MMP2 axis in non-small cell lung cancer. Oncotarget. 2013;4:2512–22.

  25. 25.

    Zhang Y, Bao C, Mu Q, Chen J, Wang J, Mi Y, et al. Reversal of cisplatin resistance by inhibiting PI3K/Akt signal pathway in human lung cancer cells. Neoplasma. 2016;63:362–70.

  26. 26.

    Sylvester PW. Targeting met mediated epithelial-mesenchymal transition in the treatment of breast cancer. Clin Transl Med. 2014;3:30.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 81773133, 81572824, 81672931, and 81673007), the Natural Science Foundation of Heilongjiang Province (No. H2016051 and H2017035), the Wu Liande Youth Science Foundation (No. WLD-QN1705), the Postdoctoral Foundation of Heilongjiang Province (No. LBH-Z18196 and LBH-Q16162), and the Science and Technique Foundation of Education Department of Heilongjiang Province (No. 12531258).

Author information

TZ, CL, JG, QM, SX, and FZ performed experiments, collected data, and analyzed data. TZ, CL, and YC wrote the manuscript. SJ, JS, BP, and FM performed experiment and analyzed the data. FL and YY designed and supervised the experiments. All authors read and approved the final manuscript.

Correspondence to Fang Liu.

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