Hormones and Signal Transduction
The tumor environment places enormous stress on cancer cells. MCCBP members are involved in studies of cellular responses to stress, gene expression, and signal transduction in normal and tumor cells. Signal transduction and subsequent changes in gene expression within cells is a primary control for growth and differentiation, and its dysfunction in cancer cells is of particular interest to many program members.
- Tumor-suppressor genes phosphatase and tensin homolog deleted on chromosome 10 (Pten) and androgen upregulated gene 19 (U19), which encodes ELL-associated factor 2 (EAF2), are frequently inactivated or downregulated in advanced prostate cancers. Pten+/- and EAF2+/- mice were crossed in the C57/BL6 background to generate EAF2-/-Pten+/-, Pten+/-, EAF2-/- and wild-type mice. Analysis of prostate tissue in these mice demonstrated that concomitant loss of EAF2 function and inactivation of one Pten allele induced spontaneous prostate cancer in 33% of the mice. Prostatic tissues from intact EAF2-/- Pten+/- mice exhibited higher levels of phospho-Akt, -p44/42 and microvessel density. Moreover, phospho-Akt remained high after castration. Consistently, there was a synergistic increase in prostate epithelial proliferation in both intact and castrated EAF2-/-Pten+/- mice. Co-downregulation of EAF2 and Pten occurred in >50% clinical prostate cancer specimens with Gleason scores of 8-9 (n=11), which is associated with poor prognosis. (Ai et. al., Oncogene. 2014 May 1;33(18):2286-94.)
- Hypoxia promotes angiogenesis, proliferation, invasion, and metastasis of pancreatic cancer. Results indicate that hypoxia inducible factor (HIF)2α is expressed early in pancreatic lesions both in human and in a mouse model of pancreatic cancer. To examine the role of HIF2α in Kras-induced pancreatic neoplasia, the Ptf1aCre transgene was used to activate Kras(G12D) and Hif2α was deleted solely within the pancreas. Surprisingly, loss of Hif2α in this model led to markedly higher, rather than reduced, number of low-grade pancreatic intraepithelial neoplasia (mPanIN) lesions. These lesions, however, failed to progress to high-grade mPanINs, and displayed exclusive loss of β-catenin and SMAD4. The relationship among HIF2α, β-catenin, and Smad4 was further confirmed in vitro, where silencing of Hif2α resulted in reduced β-catenin and Smad4 transcript levels. Thus, with oncogenic Ras expressed in the pancreas, HIF2α modulates Wnt-signaling during mPanIN progression by maintaining appropriate levels of both Smad4 and β-catenin. (Criscimanna et. al., Cancer Res. 2013 Aug 1;73(15):4781-90.)
- The transcription factor Krüppel-like factor 4 (KLF4) is an important regulator of cell-fate decision, including cell-cycle regulation, apoptosis, and stem cell renewal, and plays an ambivalent role in tumorigenesis as a tissue-specific tumor suppressor or oncogene. It was found that the Von Hippel-Lindau gene product, pVHL, physically interacts with KLF4 and regulates its rapid turnover observed in both differentiated and stem cells. pVHL depletion in colorectal cancer cells leads to cell-cycle arrest concomitant with increased transcription of the KLF4-dependent p21 gene. Immunohistochemical staining revealed elevated pVHL and reduced KLF4 levels in colon cancer tissues. We therefore propose that unexpectedly pVHL, via the degradation of KLF4, is a facilitating factor in colorectal tumorigenesis. (Gamper et. al., Mol Cell. 2012 Jan 27;45(2):233-43.)