A potential role for the Hippo pathway protein, YAP, in controlling proliferation, cell cycle progression, and autophagy in BCPAP and KI thyroid papillary carcinoma cells

Purpose: The aims were two-fold: first, to examine the expression of Yes-activated protein (YAP), a key Hippo pathway regulator, in clinical thyroid papillary carcinoma samples and to correlate this with clinicopathological parameters; second, to explore the role of YAP in regulating cell growth and division in vitro. Methods and results: YAP expression was determined by immunohistochemistry of clinical thyroid papillary carcinoma tissue microarrays and expression was correlated with clinicopathological parameters. YAP expression positively correlated with TNM stage and lymph node metastasis. The effect of YAP gene silencing by siRNA on BCPAP and KI cell migration, invasion, apoptosis, cell cycle progression (including expression of the cell cycle regulators, p21, p27, c-Myc, and Foxo3a1), and the expression of autophagy markers (Belcin1, LC3-I, LC3-II, Atg12, Atg16L1, and Atg5) were examined. YAP gene silencing decreased cell proliferation, migration, and invasion. In contrast, there was no effect on cell apoptosis, but cells arrested at G0/G1, and this was accompanied by down-regulation of c-Myc and Foxo3a and up-regulation of the cell cycle proteins, p21 and p27. The autophagy marker LC3-I was expressed at slightly higher levels than LC3-II; YAP silencing decreased both LC3-1 and LC3-II protein expression, resulting in an increase in the LC3-II/LC3-I ratio, this process was accompanied by decreases in Beclin1 and Atg5-Atg12-Atg16 complex expression. Conclusions: In papillary thyroid cancer YAP protein expression is positively correlated with the extent of TNM stage and positive lymph node metastasis. In thyroid cancer cell lines YAP appears to be important in stimulating cell proliferation while inhibiting autophagy.