PMID- 28604655 OWN - NLM STAT- MEDLINE DCOM- 20171107 LR - 20230216 IS - 1530-0307 (Electronic) IS - 0023-6837 (Linking) VI - 97 IP - 11 DP - 2017 Nov TI - Brain-derived neurotrophic factor/tropomyosin-related kinase B signaling pathway contributes to the aggressive behavior of lung squamous cell carcinoma. PG - 1332-1342 LID - 10.1038/labinvest.2017.45 [doi] AB - 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. FAU - Ozono, Keigo AU - Ozono K AD - Department of Anatomic Pathology, Kyushu University, Fukuoka, Japan. AD - Department of Surgery and Oncology, Kyushu University, Fukuoka, Japan. FAU - Ohishi, Yoshihiro AU - Ohishi Y AD - Department of Anatomic Pathology, Kyushu University, Fukuoka, Japan. FAU - Onishi, Hideya AU - Onishi H AD - Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. FAU - Nakamura, Katsuya AU - Nakamura K AD - Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. AD - Department of Thoracic Surgery, Japan Community Health Care Organization, Kyushu Hospital, Fukuoka, Japan. FAU - Motoshita, Junichi AU - Motoshita J AD - Department of Diagnostic Pathology, Hamanomachi Hospital, Fukuoka, Japan. FAU - Kato, Masato AU - Kato M AD - Department of Surgery, Hiramatsu Hospital, Saga, Japan. FAU - Nakanishi, Ryoichi AU - Nakanishi R AD - Department of Oncology, Immunology and Surgery, Graduate School of Medical Sciences and Medical School, Nagoya City University, Nagoya, Japan. FAU - Nakamura, Masafumi AU - Nakamura M AD - Department of Surgery and Oncology, Kyushu University, Fukuoka, Japan. FAU - Oda, Yoshinao AU - Oda Y AD - Department of Anatomic Pathology, Kyushu University, Fukuoka, Japan. LA - eng PT - Comparative Study PT - Journal Article DEP - 20170612 PL - United States TA - Lab Invest JT - Laboratory investigation; a journal of technical methods and pathology JID - 0376617 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Membrane Glycoproteins) RN - 0 (NTRK1 protein, human) RN - 0 (Neoplasm Proteins) RN - 0 (Recombinant Proteins) RN - 7171WSG8A2 (BDNF protein, human) RN - EC 2.7.10.1 (Receptor, trkA) RN - EC 2.7.10.1 (Receptor, trkB) RN - EC 2.7.10.1 (Receptor, trkC) RN - EC 2.7.10.1 (tropomyosin-related kinase-B, human) SB - IM MH - Brain-Derived Neurotrophic Factor/antagonists & inhibitors/genetics/*metabolism MH - Carcinoma, Squamous Cell/diagnosis/*metabolism/pathology/surgery MH - Cell Line, Tumor MH - Cell Proliferation MH - Female MH - Humans MH - Lung/*metabolism/pathology/surgery MH - Lung Neoplasms/diagnosis/*metabolism/pathology/surgery MH - Male MH - Membrane Glycoproteins/*agonists/antagonists & inhibitors/genetics/metabolism MH - Middle Aged MH - Neoplasm Grading MH - Neoplasm Invasiveness/pathology MH - Neoplasm Proteins/*agonists/antagonists & inhibitors/genetics/metabolism MH - Neoplasm Staging MH - Prognosis MH - RNA Interference MH - Receptor, trkA/genetics MH - Receptor, trkB/*agonists/antagonists & inhibitors/genetics/metabolism MH - Receptor, trkC/metabolism MH - Recombinant Proteins/chemistry/metabolism MH - Retrospective Studies MH - *Signal Transduction EDAT- 2017/06/13 06:00 MHDA- 2017/11/08 06:00 CRDT- 2017/06/13 06:00 PHST- 2016/09/25 00:00 [received] PHST- 2017/03/14 00:00 [revised] PHST- 2017/03/21 00:00 [accepted] PHST- 2017/06/13 06:00 [pubmed] PHST- 2017/11/08 06:00 [medline] PHST- 2017/06/13 06:00 [entrez] AID - S0023-6837(22)00762-0 [pii] AID - 10.1038/labinvest.2017.45 [doi] PST - ppublish SO - Lab Invest. 2017 Nov;97(11):1332-1342. doi: 10.1038/labinvest.2017.45. Epub 2017 Jun 12.