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Lymphatic metastasis-related TBL1XR1 enhances stemness and metastasis in gastric cancer stem-like cells by activating ERK1/2-SOX2 signaling

Oncogene volume 40, pages 922–936 (2021)Cite this article

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Abstract

The poor prognosis of gastric cancer (GC) results largely from metastasis and chemotherapy resistance. Toward novel therapeutic strategies that target or evade these phenomena, we evaluated the function of the transcriptional regulator transducin (β)-like 1 X-linked receptor 1 (TBL1XR1) in GC cells, including stem-like cells. In this study, the correlation of expression of TBL1XR1 and clinical features and GC patients’ outcomes was evaluated. Knockdown or exogenous expression of TBL1XR1 was combined with in vitro (2D and 3D cultures) and in vivo (mouse lung and lymphatic metastasis models) assays to evaluate the function of TBL1XR1. TBL1XR1’s downstream signaling was delineated by phospho-kinase array and knockdown of candidate mediators. Analysis of clinical data showed that TBL1XR1 overexpression was correlated with worse prognosis. Functional assays showed that TBL1XR1 promoted stemness, epithelial–mesenchymal transition (EMT), and lung and lymphatic metastasis in GC cells. TBL1XR1 activated ERK1/2-Sox2 signaling and was dependent on signaling via PI3K/AKT, in GC stem-like cells distinguished by CD44 expression. Moreover, inhibition of these signaling proteins reversed chemoresistance in in vitro and in vivo models. Taken together, our results indicate that TBL1XR1 promotes stemness and metastasis in GC, making it a potential prognostic indicator. The PI3K/AKT-TBL1XR1-ERK1/2-Sox2 axis may represent a target for the treatment of GC.

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Fig. 1: Expression of transducin (β)-like 1 X-linked receptor 1 (TBL1XR1) and CD44 in tumors correlates with overall survival of GC patients.
Fig. 2: TBL1XR1 expression correlates with CSC phenotypes, EMT, and invasive properties in gastric epithelial and GC cells.
Fig. 3: TBL1XR1 controls CSC phenotypes and EMT in human GC cells.
Fig. 4: TBL1XR1 is regulated by PI3K/AKT and regulates ERK1/2 in human GC cells.
Fig. 5: TBL1XR1 knockdown reverses chemoresistance in vitro and in mouse xenograft models.
Fig. 6: TBL1XR1 knockdown reduces EMT and CSC phenotypes in mouse organoids and inhibits lung metastasis.
Fig. 7: TBL1XR1 regulates lymphatic metastasis in vitro and in vivo.

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Acknowledgements

This research was supported by NIH/NCI through 1R01 CA158301-01 (SSY), Cancer Center Support Grant P30 CA008748 (MSKCC), and Natural Science Foundation of Fujian Province (2019J01155). Authors thank Jessica Moore, MS, senior editor and grant writer at MSK, for help in editing and revising the manuscript.

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  1. These authors contributed equally: Jun Lu, Heejin Bang, Su Mi Kim

Authors and Affiliations

  1. Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Jun Lu, Sam S. Yoon & Changhwan Yoon

  2. Department of Gastric Surgery, Fujian Medical University Union Hospital, Fujian, China

    Jun Lu & Chao-hui Zheng

  3. Department of Pathology, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, South Korea

    Heejin Bang

  4. Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea

    Su Mi Kim & Jun Ho Lee

  5. Department of Surgery, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Gyeonggi-do, South Korea

    Su Mi Kim

  6. Department of Internal Medicine, Liver Research Institute, Seoul National University Hospital, Seoul, South Korea

    Soo-Jeong Cho

  7. Department of Medicine, Howard University, Washington, DC, USA

    Hassan Ashktorab & Duane T. Smoot

  8. Department of Cancer Biology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    Sandra W. Ryeom

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Lu, J., Bang, H., Kim, S.M. et al. Lymphatic metastasis-related TBL1XR1 enhances stemness and metastasis in gastric cancer stem-like cells by activating ERK1/2-SOX2 signaling. Oncogene 40, 922–936 (2021). https://doi.org/10.1038/s41388-020-01571-x

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