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

Cancer Gene Therapy volume 27, pages 136–146 (2020)Cite this article

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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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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).

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  1. These authors contributed equally: Tiewa Zhang, Cheng Liu, Yan Yu

Authors and Affiliations

  1. Department of Thoracic Surgery, The First Affiliated Hospital of Harbin Medical University, 150001, Harbin, China

    Tiewa Zhang

  2. Department of Thoracic Surgery, The Fourth Affiliated Hospital of Harbin Medical University, 150001, Harbin, China

    Cheng Liu

  3. Department of Medical Oncology, Harbin Medical University Cancer Hospital, 150081, Harbin, China

    Yan Yu, Jianxiong Geng, Qingwei Meng, Shanqi Xu, Fengrui Zhou, Bo Pan & Fang Liu

  4. Department of Gastroenterology, The First Affiliated Hospital of Harbin Medical University, 150001, Harbin, China

    Yingying Chen

  5. Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 518116, Shenzhen, China

    Shi Jin

  6. Department of Oncology, The Second Clinical Medical College, Shenzhen People’s Hospital of Jinan University, 518116, Shenzhen, China

    Jing Shen

  7. Department of Medical Gynecology, Harbin Medical University Cancer Hospital, 150081, Harbin, China

    Fanling Meng

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Contributions

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.

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Correspondence to Fang Liu.

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Zhang, T., Liu, C., Yu, Y. et al. TBL1XR1 is involved in c-Met-mediated tumorigenesis of human nonsmall cell lung cancer. Cancer Gene Ther 27, 136–146 (2020). https://doi.org/10.1038/s41417-019-0111-0

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