Expression and significance of Hippo/YAP signaling in glioma progression

Abstract

Dysregulation of Hippo/YAP signaling leads to aberrant cell growth and neoplasia. Although the roles and regulation of Hippo/YAP signaling were extensively studied in cancer biology recently, study systematically checking the expression pattern of core components of this pathway at the tumor tissue level remains lacking. In this study, we thoroughly examined the profile of core components of Hippo/YAP signaling in patient specimens both at the mRNA and at protein levels. We found that the mRNA level of YAP1/TAZ and their target genes, CRY61, CTGF, and BIRC5, was remarkably amplified in glioma tissues. Consistently, the protein level of YAP1/TAZ increased and meanwhile those of p-YAP1/p-TAZ and LATS1/2 decreased in gliomas. Unexpectedly, both the mRNA and protein levels of MST1/2 increased in the glioma tissues, inconsistent with its presumed tumor suppressor identity. In addition, over-expression of LATS2 decreased, while over-expression of YPA1 increased the cell proliferation ability. Furthermore, based on the data from the free public database, YAP1/TAZ and BIRC5 were positively associated with the prognosis of glioma patients, while LATS1/2 exhibited negative correlation with the glioma patient prognosis. Collectively, we deduce that, in glioma tissue context, MST1/2 may not be the essential component of the hippo/YAP pathway. Moreover, our findings uncover a new evidence supporting that YAP1/TAZ-BIRC5 might be abnormally activated due to LATS1/2 down-regulation, which in turn promote the occurrence and development of gliomas, paving the way to identify the potential therapeutic molecular target for gliomas.

<p>Role of Hippo/YAP signaling in irradiation-induced glioma cell apoptosis</p>

“…For example, it acts as an oncogene in liver, 23 pancreas 24 cancers, whereas it exerts as a tumor suppressor in some breast cancers. 25 In glioma, YAP1 and their target genes, CRY61, CTGF, and BIRC5 were identified to be significantly amplified in glioma tissues, and upregulation of YPA1 enhanced cell proliferation ability and conferred glioma cells cisplatin-resistance, [26][27][28] illustrating that YAP1 plays a role in glioma chemosensitivity. Moreover, Zhang et al 29 reported that inhibition of TAZ, an effector of Hippo signaling significantly promoted radiation-induced senescence and growth inhibition in glioma cells, suggesting a vital role of Hippo signaling plays in glioma radiosensitivity.…”

Fatal correlation between YAP1 expression and glioma aggressiveness: clinical and molecular evidence

“…While it is now well established that YAP1 is strongly involved in tumorigenesis, notably by regulating cell proliferation, its role in gliomas remains poorly investigated . Currently, several studies have demonstrated the implication of YAP1 in glioma cell proliferation using shRNA or overexpression‐based approaches . However, these studies were performed on conventional glioma cell lines (U87 and U251) that had been isolated long before use and no longer accurately reflected the initial pathology .…”

Overexpression of the YAP1 oncogene in clear cell renal cell carcinoma is associated with poor outcome

“…Furthermore, they observed that overexpression of LATS1 downregulated the YAP1 protein level, inhibited cell proliferation, induced cell apoptosis and cell cycle arrest in 786-O cells (39). LATS1 downregulation and its contribution to cancer progression has been observed in other malignances such as glioma (40), nosopharyngeal carcinoma (41), astrocytoma (42), non-small cell lung cancer (18), breast cancer (16), colorectal cancer (17) and renal carcinoma (39). Additionally, association between LATS1 hypermethylation and tumor progression has been noted in lung cancer (43), schwannomas (44), oral squamous cell carcinoma (45), colorectal cancer (17) and astrocytoma (42), however, the authors did not observe the influence of LATS1 methylation status on patient outcome.…”