(2012-2016) – Principal Investigator for IVN Anca Botezatu, PhD.

Aim: To analyze the MLL gene family members’ involvement in pancreatic cancer and neuroendocrine pancreatic tumors.

Partners: Coordinator:– “ Fundeni Clinical Institute,  project director Prf Irinel Popescu, PhD

Partner 1 – SC RNTECH SRL, responsible Anca Nastase

Partner 2 – The Institute Of Cellular Biology And Pathology N. Simionescu, responsible Luminita Ivan PhD

Partner 3 – „Stefan S. Nicolau” Institute of Virology, responsible Anca Botezatu, PhD

Partner 4 – “Prof. Dr. Al. Trestioreanu” Institute of Oncology, responsible Adina Stanciu PhD

Working team: Botezatu A, Chivu M, Bleotu C, Diaconu C, Plesa A, Iancu I, Huica I, Aldea I

Funding: IVN=650 000 LEI

Project PNCDI2 90-2012

Implementation period: dec.2012 – dec.2016

Summary: Pancreatic cancer is the fourth leading cause of cancer death and has a very poor prognosis; the five year survival rate of less than 5%. The molecular mechanisms of this disease remain poorly understood. Pancreatic ductal adenocarcinoma is highly resistant to conventional treatment modalities such as systemic chemo- and radiation therapy. The current compendium of validated genetic mutations has provided a multistep model for the initiation and progression of pancreatic adenocarcinoma that is typified by the near-universal and early occurrence of activating mutations in KRAS and frequent later-stage inactivation of p16INK4A, p53, and/or SMAD4. Pancreatic cancer is not only a disease with a genetic background, but also is correlated to epigenetic alterations such as DNA methylation and histone modifications, leading to an altered gene expression. Altered gene expression due to changes in the compact chromatin structure and posttranslational histone modifications has often been considered as a significant contributing factor for tumor development. Progression of pancreatic cancer, which has a very poor prognosis, is found to be associated with a host of changes in gene expression. Chromatin status is modulated by epigenetic mechanisms, making DNA more or less accessible to the transcriptional machinery. There are five major mechanisms known that alter chromatin architecture: DNA methylation, post-translational histone modifications, use of histone variants, chromatin remodeling and incorporation of non-coding RNA into chromatin.

The objectives:

– Genomic and epigenomic studies of MLL members family (mutations and genes promoters methylation) associated with pancreatic cancer and metastasis (samples from primary tumor / metastasis and cell culture mutations screening).

– Characterization of chromatin remodeling complexes formed by interaction of MLL genes, H3K4 3me and RNA Pol II with specific activated genes and factor involved in transcription inactivation (H3K27 and H3K9 3me), using chromatin immunoprecipitation technique.

– Evaluation of mutant variants of MLL genes effects on transcription activation of specific controlled genes in vitro models (pancreatic cancer cell lines/ pancreatic neuroendocrine tumors lines), and they relation with invasion and metastasis.

Results:

1. Anca Botezatu, Coralia Bleotu, Anca Nastase, Gabriela Anton, Nicolae Bacalbasa, Dan. Duda, Simona Dima, Irinel Popescu. CpG islands promoter methylation the main cause for GNMT gene decreased expression in pancreatic adenocarcinoma FEBS EMBO 2014 Conference, 30 August-4 September 2014, Paris, France in FEBS Journal 281 (Suppl s1), p 299. ISSN: 1742-4658. IF=5.622
2. Veronica Ilie, Valeria Tica, Radu Florea, Andrei Sorop, Luinita Ivan, Elena Uyy, Viorel Suica, Felicia Antohe, Nicolae Bacalbasa, Mihai Eftimie, Anca Nastase, Vlad Herlea, Carmen Diaconu, Coralia Bleotu, Anca Botezatu, Liliana Paslaru, Dan Duda, Irinel Popescu, Simona Dima. The predictive role of S100A4 as a prometastatic factor in pancreatic ductal adenocarcinoma adenocarcinoma. FEBS EMBO 2014 Conference, 30 August-4 September 2014, Paris, France in FEBS Journal 281 (Suppl s1), p 693-693, ISSN: 1742-4658. IF=5.622
3. Anca Botezatu, Iulia Iancu, Adriana Pleşa, Carmen C Diaconu, Gabriela Anton, Radu Florea, Andrei Sorop, Nicolae Bacalbasa, Valeria Tica, Dan Duda, Irinel Popescu. Deregulation B-Catenin gene expression in pancreatic cancer. American Pancreatic Association, 46fh Annual Meeting, 4-7 nov 2015, San Diego USA, in Pancreas 44(8) pg 1362. ISSN 1536-4828. IF=3.327
4. Anca Botezatu, Iulia Iancu, Adriana Plesa, Gabriela Anton, Raluca Florea, Veronica Ilie, Andrei Sorop, Nicolae Bacalbasa, Valeria Tica, Simona Dima, Irinel Popescu. Factors involved in B-Catenin gene expression deregulation in pancreatic cancer. Acad Nicolae Cajal Symposium, Conferinta de medicina translationala, 1-4 aprilie 2015, Abstract aparut in Culegerea de rezumate, 2015, pg 27
5. Anca Botezatu, Iulia Iancu, Adriana Plesa, Carmen C. Diaconu, Gabriela Anton, Raluca Florea, Veronica Ilie, Andrei Sorop, Nicolae Bacalbasa, Valeria Tica, Simona Dima, Irinel Popescu. Β-catenin gene expression deregulation in pancreatic adenocarcinoma.  EACR Conference Series, Berlin, Germany – Abstract publicat in Basis epigenetic mechanisms in cancer, 2015, P15
6. Anca Botezatu, Coralia Bleotu, Anca Nastase, Gabriela Anton, Nicolae Bacalbasa, Dan Duda, Simona O Dima, Irinel Popescu. Epigenetic Silencing of GNMT Gene in Pancreatic Adenocarcinoma. Cancer Genomics Proteomics. 2015;12(1):21-30. IF=3.395
7. Anca Nastase, Simona Dima, Valeria Tica, Raluca Florea, Andrei Sorop, Veronica Ilie, Mihai Eftimie, Liliana Paslaru, Vlad Herlea, Nicolae Bacalbasa, Luminita Ivan, Elena Uyy, Viorel Iulian Suica, Felicia Antohe, Iulia V Iancu, Adriana Plesa, Anca Botezatu, Dan G Duda,Carmen C Diaconu. S100A4 and ERBB2 as Co-Factors in Pancreatic Cancer, J. Transl. Med. Res 2016; 21(4):259-266 doi: 10.21614/jtmr-21-4-100 IF=0.106
8. Anca Botezatu, Iulia V Iancu, Adriana Plesa, Carmen C Diaconu, Gabriela Anton, Raluca Petre, Veronica Ilie, Andrei Sorop, Nicolae Bacalbasa, Valeria Tica, Simona O Dima, Irinel Popescu. Possible epigenetics biomarkers in pancreatic oncogenesis. Academician Nicolae Cajal Symposium of the Academy of Medical Sciences Romanian Academy Library, March 17 – 19, 2016. comunicare
9. Iulia Virginia Iancu, Anca Botezatu, Adriana Pleşa, Carmen C Diaconu, Gabriela Anton, Raluca Florea, Veronica Ilie, Andrei Sorop, Valeria Tica, Simona Olimpia Dima, Irinel Popescu.  LncRNAs expression profiles in pancreatic cancer. Epigenetic Alterations in Human Thyroid Oncogenesis. European Human Genetics Conference (ESHG,) 2016, Barcelona, Spain, abstract in European Journal of Human Genetics, vol 24-E supp 1, 2016 p 365, P17.33, ISSN: 1018-4813, IF= 5.351