Spinophilin expression determines cellular growth, cancer stemness and 5-flourouracil resistance in colorectal cancer
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Anna Lena Ress1,*, Verena Stiegelbauer1,*, Daniela Schwarzenbacher1, Alexander Deutsch2, Samantha Perakis1, Hui Ling3, Cristina Ivan4, George Adrian Calin3,4, Beate Rinner5, Armin Gerger1 and Martin Pichler1,3
1 Division of Oncology, Department of Internal Medicine, Medical University of Graz, Austria
2 Division of Haematology, Department of Internal Medicine, Medical University of Graz, Austria
3 Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, TX, USA
4 Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, TX, USA
5 Center for Medical Research, Medical University of Graz, Graz, Austria
* These authors contributed equally to this work
Martin Pichler, email:
Keywords: colorectal cancer, prognosis, cellular growth
Received: June 23, 2014 Accepted: August 07, 2014 Published: August 08, 2014
The putative tumor suppressor gene spinophilin has been involved in cancer progression in several types of cancer. In this study, we explored the prognostic value of spinophilin expression in 162 colon adenocarcinoma patients. In addition, we generated stably expressing spinophilin-directed shRNA CRC cell lines and studied the influence of spinophilin expression on cellular phenotypes and molecular interactions. We independently confirmed that low spinophilin expression levels are associated with poor prognosis in CRC patients (p = 0.038). A reduction of spinophilin levels in p53 wild-type HCT116 and p53-mutated Caco-2 cells led to increased cellular growth rates and anchorage-independent growth (p<0.05). At molecular level, reduced spinophilin levels increased the expression of the transcription factor E2F-1. In addition, we observed an increased formation of tumor spheres, increased number of CD133 positive cells and an increased resistance to 5-flourouracil (p<0.05). Finally, treatment with the de-methylating agent 5-aza-dC increased spinophilin expression in CRC cells (p<0.05), corroborated by a correlation of spinophilin expression and extent of methylated CpG sites in the gene promoter region (p<0.001). In conclusion, gain of aggressive biological properties of CRC cells including cellular growth, cancer stem cell features and 5-flourouracil resistance partly explains the role of spinophilin in CRC.
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