Proliferative role of BDNF/TrkB signaling is associated with anoikis resistance in cervical cancer.

Abstract

Brain-derived neurotrophic factor (BDNF) is known as one of the members of the neurotropin family. BDNF-induced activation of its receptor tyrosine kinase B (TrkB) is associated with anoikis tolerance, tumor progression and poor prognosis in many types of malignancy. However, to the best of our knowledge, there are no reports describing the contribution of the BDNF/TrkB axis to cervical cancer. BDNF and TrKB expression in cervical cancer (CC) tissues and adjacent normal tissues from 87 patients were analyzed by immunohistochemistry, western blot analysis and quantitative PCR assays and the results showed that they were significantly higher in cancer tissues than that in normal adjacent tissues, respectively. Higher expression rates of BDNF and TrKB were observed in stage IIB or higher and BDNF expression was positively associated with lymph node metastasis. Notably, a high expression of TrKB may be contributed to poor survival time, which confirmed by Kaplan-Meier analysis. Compared to the corresponding CC cell lines, HeLa, SiHa, CASKI, C4-1 and C-33a, BDNF and TrKB expression was enhanced in anoikis-like apoptotic tolerance (AAT), a cell model established from cervical cancer cell lines. AAT cells showed a higher proliferation activity compared with CC cell lines, which was confirmed by a shorter G0/G1 phase, elevated cyclin A, cyclin D1 and c-myc, decreased caspase-3 and Bax, and increased Bcl-2. By contrast, the knockdown of TrKB expression reversed these changes in AAT cells, induced G0/G1 arrest and suppressed proliferation activity. The results of the present study show that PI3K/Akt signaling is involved in the BDNF/TrKB-induced proliferation of AAT cells in cervical cancer. These findings indicate that BDNF/TrKB pathway is a potential target for the treatment of cervical cancer.