PAX6 Is Expressed in Pancreatic Cancer and Actively Participates in Cancer Progression through Activation of the MET Tyrosine Kinase Receptor Gene

Abstract

Tumors of the exocrine pancreas have a poor prognosis. Several proteins are overexpressed in this cancer type, including the MET tyrosine kinase receptor and the transcription factor PAX6. In this report, we find that PAX6(5a), an alternately spliced variant form of PAX6, is expressed in pancreatic carcinoma cell lines at higher levels than the canonical PAX6 protein. Both protein forms of PAX6 bind directly to an enhancer element in the MET promoter and activate the expression of the MET gene. In addition, inhibition of PAX6 transcripts leads to a decline in cell growth and survival, differentiation, and a concurrent reduction of MET protein expression. These data support a model for a neoplastic pathway, where expression of a transcription factor from development activates the MET receptor, a protein that has been directly linked to protumorigenic processes of resisting apoptosis, tumor growth, invasion, and metastasis.Pancreatic cancer is an aggressive and deadly disease, with an average median survival of less than a year (1). Several genetic pathways have been identified as being active in the progression of this tumor, including signaling through MET (MET tyrosine kinase receptor protein). The MET gene encodes a tyrosine kinase receptor for the ligand hepatocyte growth factor/scatter factor. The MET gene produces a partially glycosylated 170-kDa precursor protein. This precursor is glycosylated further and cleaved into a 50-kDa ␣ chain and a 140-kDa ␤ chain to create a mature receptor (2). The MET receptor is essential for normal development and plays a role in cell migration, growth, survival, differentiation, angiogenesis, and tube formation/ branching morphogenesis (reviewed in Ref.3). MET has also been implicated in cancer progression and is directly involved in metastasis, resistance to apoptosis, and tumor growth.MET is expressed in the developing pancreatic bud of the embryo and marks candidate stem/progenitor cells in the embryonic and adult pancreas (4 -6). MET expression is expressed at very low levels in normal adult differentiated pancreatic cells (7). MET is overexpressed in pancreatic cancer cells and has been linked to the aggressiveness of this tumor in terms of growth, invasion, and metastasis (7-10).Although mutations in the MET locus have been identified, overexpression of MET occurs mainly due to aberrant transcriptional regulation (3). The MET gene is regulated by several transcription factors that can either activate or repress expression. Activators include HIF1 (hypoxia-induced factor 1) in response to oxygen deficiency (11), ETS1 (12), Sp1 (13), AP1 (14), Smads downstream of transforming growth factor-␤ signaling (13), and the p53 protein (15) The transcription factor PAX3 can also activate MET expression during the embryonic development of muscle cells (23). PAX3 belongs to the PAX gene family, and most of what is known about these related proteins is their role during development. Only recently has the expression of PAX proteins in adult stem cells and in disease been discovered...

Possible role of Pax-6 in promoting breast cancer cell proliferation and tumorigenesis

“…These experiments showed that decreased Pax6 expression resulted inremarkable suppression of in vitro cell growth and in vivo tumorigenesis. Our observations were in consistency with that in previous report about pancreatic cancer (13). Disturbed regulation of the cell cycle is a hallmark of cancers.…”

“…It should be noted that Pax6 has three different protein isoforms: normal Pax6, Pax6 (5a), and paired domain-less Pax6 (ΔPD) (20). Thereinto, Pax6 (5a) is expressed in pancreatic carcinoma cell lines at higher levels than the canonical Pax6 protein (13). Yet it is still unknown if there is any difference in expression levels or functional roles in breast cancer for individual variants.…”

“…In a study of pancreatic cancers, both protein forms of Pax6 can transactivate the expression of Met oncogene that commonly overexpressed in many cancers. And downregulation of Pax6 results in a decline in cancer cell proliferation and Met protein expression (13). In addition, Pax6 was found to be directly linked to glioblastoma, bladder cancer and prostate cancer, suggesting that Pax6 may function as a tumor suppressor and serve as a molecular biomarker for cancer development (14,15).…”

“…In a cancer-wide analysis of Pax gene expression in a panel of common cancer cell lines, Pax6 gene was expressed at high levels in breast and other cancer cells (17). In these regards, Pax6 may play a crucial role in regulating breast cancer cell growth by interacting with some important molecules such as Met and AR (13,15). Yet the functional role of Pax6 in breast cancer carcinogenesis has not been addressed.…”

PAX6 overexpression is associated with the poor prognosis of invasive ductal breast cancer

“…In addition, PAX6 was upregulated in alveolar soft part sarcoma, a type of cancer with an extremely poor prognosis (20). In pancreatic cancer, PAX6 actively participates in tumor growth via the MET tyrosine kinase (21). However, certain studies have suggested that PAX6 may have a tumor suppressor effect, such as in glioblastoma (22,23).…”