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Tropomyosin-related kinase B promotes distant metastasis of colorectal cancer through protein kinase B-mediated anoikis suppression and correlates with poor prognosis

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Abstract

An increasing amount of evidence demonstrated that the neurotrophic receptor tropomyosin-related kinase B (TrkB) plays a critical role in the development and progression of multiple types of cancer. However, its underlying mechanism in distant metastasis through the circulatory and lymphatic systems in colorectal cancer (CRC) is still unclear. Here we showed that downregulation of TrkB using short hairpin RNA obviously increased anoikis (detachment-induced apoptosis resulting from loss of cell–matrix interactions) sensitivity of CRC cells in vitro. Furthermore, using tail vein injection model, we confirmed that silencing TrkB significantly inhibited metastasis of CRC cells in vivo. Conversely, overexpression of TrkB obviously protected CRC cells from anoikis in vitro. Both loss- and gain-of-functional experiments indicated that TrkB could be a functional molecule in anti-anoikis of CRC cells. Mechanistically, we found that protein kinase B (PKB, also known as Akt) signaling pathway was a functional link in TrkB-induced anoikis suppression in CRC cells. Phosphorylation levels of Akt are closely related with the expression pattern of TrkB in CRC cells and inhibition of Akt activation robustly induces anoikis of CRC cells in vitro. In addition, our clinical investigation showed that high TrkB expression levels in CRC patients were associated with lymph node metastasis, distant metastasis and unfavourable prognosis. Thus, based on our results, this study suggests that an important function of TrkB is to protect CRC cells from anoikis in the circulatory and lymphatic systems, and that TrkB could be a promising candidate in CRC therapy, especially in the inhibition of cancer metastasis.

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (Nos. 30901786, 81172010). We thank **aofang Zhang for her excellent technical assistance. We also thank the patients who gave consent to use their tissue for research.

Conflict of interest

None declared.

Author information

Authors and Affiliations

  1. ****g Hospital of Digestive Diseases, Fourth Military Medical University, **’an, 710032, China

    Meng Fan, Weizhong Wang & Jipeng Li

  2. State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, **’an, 710032, China

    Jianyong Sun, Lei Wang, **ang Zhang, Angang Yang & Rui Zhang

  3. Department of Operative Dentistry and Endodontics, School of Stomatology, Fourth Military Medical University, **’an, 710032, China

    Wei Wang

  4. Department of Vascular and Endocrine Surgery, ****g Hospital, Fourth Military Medical University, **’an, 710032, China

    **g Fan

  5. Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, **’an, 710038, China

    Jianyong Sun

  6. Department of Immunology, Fourth Military Medical University, **’an, 710032, China

    Angang Yang

  7. Department of General Surgery, The 456th Hospital of PLA, **an, 250000, China

    Meng Fan

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  1. Meng Fan
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Correspondence to Weizhong Wang, Rui Zhang or Jipeng Li.

Additional information

Meng Fan, Jianyong Sun, Wei Wang and **g Fan have contributed equally to this work.

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Fan, M., Sun, J., Wang, W. et al. Tropomyosin-related kinase B promotes distant metastasis of colorectal cancer through protein kinase B-mediated anoikis suppression and correlates with poor prognosis. Apoptosis 19, 860–870 (2014). https://doi.org/10.1007/s10495-014-0968-1

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