title: SOX15 is a candidate tumor suppressor in pancreatic cancer with a potential role in Wnt/β-catenin signaling.
abstract: Pancreatic cancer is among the top five deadliest cancers in developed countries. Better knowledge of the molecular mechanisms contributing to its tumorigenesis is imperative to improve patient prognosis. Identification of novel tumor suppressor genes (TSGs) in pancreatic cancer will reveal new mechanisms of pathway deregulation and will ultimately help improve our understanding of this aggressive disease. According to Knudson's two-hit model, TSGs are classically disrupted by two concerted genetic events. In this study, we combined DNA methylation profiling with copy number and mRNA expression profiling to identify novel TSGs in a set of 20 pancreatic cancer cell lines. These data sets were integrated for each of ∼12 000 genes in each cell line enabling the elucidation of those genes that undergo DNA hypermethylation, copy-number loss and mRNA downregulation simultaneously in multiple cell lines. Using this integrative genomics strategy, we identified SOX15 (sex determining region Y-box 15) as a candidate TSG in pancreatic cancer. Expression of SOX15 in pancreatic cancer cell lines with undetectable expression resulted in reduced viability of cancer cells both in vitro and in vivo demonstrating its tumor suppressive capability. We also found reduced expression, homozygous deletion and aberrant DNA methylation of SOX15 in clinical pancreatic tumor data sets. Furthermore, we deduced a novel role for SOX15 in suppressing the Wnt/β-catenin signaling pathway, which we hypothesize is a pathway through which SOX15 may exert its tumor suppressive effects in pancreatic cancer.
authors: BC Cancer Research Centre, Vancouver, BC, Canada.
authors: K L
authors: KL
authors: Thu
authors: Ontario Cancer Institute, Princess Margaret Hospital, University Health Network and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
authors: N
authors: N
authors: Radulovich
authors: BC Cancer Research Centre, Vancouver, BC, Canada.
authors: D D
authors: DD
authors: Becker-Santos
authors: BC Cancer Research Centre, Vancouver, BC, Canada.
authors: L A
authors: LA
authors: Pikor
authors: BC Cancer Research Centre, Vancouver, BC, Canada.
authors: A
authors: A
authors: Pusic
authors: BC Cancer Research Centre, Vancouver, BC, Canada.
authors: W W
authors: WW
authors: Lockwood
authors: BC Cancer Research Centre, Vancouver, BC, Canada.
authors: W L
authors: WL
authors: Lam
authors: Ontario Cancer Institute, Princess Margaret Hospital, University Health Network and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
authors: M-S
authors: MS
authors: Tsao
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D016513:Mice, SCID; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055747:SOX Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000235:genetics*
chemical_list: D055747:SOX Transcription Factors; C102810:SOX15 protein, human; D025521:Tumor Suppressor Proteins