Brain-derived neurotrophic factor/tropomyosin-related kinase B signaling pathway contributes to the aggressive behavior of lung squamous cell carcinoma

Abstract

The tropomyosin-related kinase (Trk) family consists of TrkA, TrkB, and TrkC, which play essential roles in tumor progression and/or suppression in various cancers. Little is known about the biological significance of the Trk family in human lung squamous cell carcinoma (SCC). Here we investigated the clinical significance of the protein expression of Trk family members in samples from 99 SCC patients, and we explored the relationship between invasion/proliferation activities and Trk expression using lung SCC cell lines to clarify the biological significance of the Trk family in lung SCC. Immunohistochemical high expression of TrkB was significantly correlated with vascular invasion (P=0.004), lymph node metastasis (P<0.001), and advanced stage (P=0.0015). The overall survival of the patients with TrkB-high expression was significantly shorter than those with TrkB-low expression (P=0.0110). TrkA/TrkC expressions were not predictors of poor prognosis. An in vitro assay demonstrated that the inhibition of brain-derived neurotrophic factor (BDNF) (a TrkB ligand) and TrkB by K252a (a Trk inhibitor) or siRNA (BDNF-siRNA, TrkB-siRNA) suppressed the invasion, migration, and proliferative activities of lung SCC cells. The administration of recombinant human BDNF (rhBDNF) enhanced the invasion, migration, and proliferation activities, which were abrogated by K252a. TrkB-siRNA transfection increased the protein expression of E-cadherin and decreased vimentin expressions in lung SCC cells. Matrix metalloproteinase-2 (MMP-2)-mediated gelatin degradations were decreased in lung SCC cells transfected with TrkB-siRNA. Thus, TrkB-high expression is an indicator of poor prognosis in lung SCC, probably due to invasion/proliferation activities promoted by the BDNF/TrkB signaling pathway, which could become a therapeutic target for lung SCC.

Hedgehog Inhibition Upregulates TRK Expression to Antagonize Tumor Suppression in Small Cell Lung Cancer Cells

“…We have shown that TRKB/BDNF signalling is a possible therapeutic target for large-cell neuroendocrine cancer (LCNEC) of the lung, which is a type of NET (4,5). In addition, we have found that TRKB/BDNF signalling contributes to a malignant phenotype in other cancers such as lung squamous cell carcinoma and gall bladder cancer (6,7). Other groups have also reported that TRKB and BDNF are associated with poor prognosis (8,9).…”

Rapamycin ameliorates psoriasis by regulating the expression and methylation levels of tropomyosin viaERK1/2 andmTORpathways in vitro and in vivo

“…Tropomyosins family has long been known for its properties in the construction of cell skeleton, but it actually has shown more functions in others cell processes, such as the pathogenesis of various tumours . It is well known that the most of gene expression could be inhibited during DNA methylation.…”

“…It consists of four different genes (TPM1‐4) and produces more than 20 TPM isoforms via alternate splicing of mRNAs . Previously studies have shown that TPMs may participate in the pathogenesis of diverse human diseases, such as cancers, autoimmunity and muscle diseases . However, the role of TPMs in psoriasis remains undetermined.…”

FAM115C could be a novel tumor suppressor associated with prolonged survival in pancreatic cancer patients

“…We evaluated the proportion and the intensity of the immunoreactive cells over the entire slides by using the Allred score (AS) 14 . We divided the immunoreactivity into four grades by the AS as follows: Grade 0, an AS of 0; Grade 1, AS of 2-4; Grade 2, AS of 5 or 6; and Grade 3, AS of 7 or 8 15,16 .…”