title: Tropomyosin-related kinase B promotes distant metastasis of colorectal cancer through protein kinase B-mediated anoikis suppression and correlates with poor prognosis.
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.
authors.affiliation: Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Fan
authors.forename: Jianyong
authors.initials: J
authors.lastname: Sun
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Jing
authors.initials: J
authors.lastname: Fan
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhang
authors.forename: Angang
authors.initials: A
authors.lastname: Yang
authors.forename: Weizhong
authors.initials: W
authors.lastname: Wang
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.forename: Jipeng
authors.initials: J
authors.lastname: Li
mesh_terms: D000818:Animals; D023102:Anoikis; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011379:Prognosis; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D020813:Receptor, trkB
chemical_list: D008562:Membrane Glycoproteins; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; D020813:Receptor, trkB; C000591259:tropomyosin-related kinase-B, human; D051057:Proto-Oncogene Proteins c-akt