Project description:That mutational activation of Kras and inactivation of p16 are two signature genetic alterations required for development of PDAC. To elucidate the downstream pathways activated by oncogenic Kras and inactivated p16 in human pancreatic tumorigenesis, we profiled gene expression in HPNE/Kras/shp16 and HPNE/Kras cells using cDNA microarray analysis.
Project description:Lung cancer is one of the most common cancers and remains a major worldwide health problem. Lung adenocarcinoma (LUAD) is the major subtype of lung cancer. Although several treatments for LUAD have been developed, still many patients lead to cancer-associated death because of uncontrollable LUAD progression. Further biological and clinical studies to elucidate molecular mechanisms associated with LUAD progression are required to resolve such problems. In this study, we screened family with sequence similarity 111 member B (FAM111B), of which precise functional role in cancers is not clear, as the molecule highly expressed in papillary predominant lung adenocarcinoma.
Project description:PTPRD is a tumor suppressor of glioma that is frequently co-deleted with CDKN2A/p16. We show that Ptprd and p16 cooperate to promote gliomagenesis in the RCAS PDGFB / Nestin tv-A glioma mouse model. We found unique gene expression changes within tumor cells of Ptprd+/-p16-/- vs. Ptprd+/+p16-/- and Ptprd-/-p16-/- tumor cells. Neonatal mice were injected with RCAS PDGFB GFP. At symptoms, or at 12 weeks post injection, GFP+DAPI- tumor cells were sorted for RNA extraction and hybridization on Affymetrix microarrays. The mouse strain used was a mixed background of C57/BL6 and FVB/N. Ptprd mice were from Uetani et al. 2000 and p16/Nestin-tvA mice were from Tchouganouva et al. 2007.
Project description:Lung cancer is a common type of cancer that represents a health problem worldwide; lung adenocarcinoma (LUAD) is a major subtype of lung cancer. Although several treatments for LUAD have been developed, the mortality rate remains high because of uncontrollable progression. Further biological and clinicopathological studies are therefore needed. Here, we investigated the role of family with sequence similarity 111 member B (FAM111B), which is highly expressed in papillary-predominant LUAD; however, its role in cancer is unclear. An immunohistochemical analysis confirmed that papillary-predominant adenocarcinomas exhibited higher expression of FAM111B, compared with lepidic-predominant adenocarcinomas. Additionally, FAM111B expression was significantly correlated with clinical progression. In vitro functional analyses using FAM111B-knockout cells demonstrated that FAM111B plays an important role in proliferation and cell cycle progression of KRAS-driven LUAD under serum-starvation conditions. Furthermore, FAM111B regulated cyclin D1-CDK4-dependent cell cycle progression by degradation of p16. In summary, we revealed the clinical importance of FAM111B in human tumor tissues, as well as its function as a degradative enzyme. Therefore, FAM111B has potential as a clinicopathological prognostic marker for LUAD.
Project description:Head and neck squamous cell carcinomas are heterogeneous neoplasms that show clinical and biological differences in association with the human papillomavirus (HPV). To provide adequate therapeutic strategies, biological and clinical characterization is essential to stratify patients based on prognostic and predictive factors. Reports on HNSCC are scarce in Mexico, thus in the present study, we analyze 414 cases of HNSCC, including those of the oropharynx (OPSCC), larynx (LASCC), and oral cavity (OCSCC). We determined the presence of HPV and p16 expression. Global expression profiles were analyzed with Affymetrix HTA 2.0 microarray in 25 selected cases HPV+/p16+ versus HPV-/p16-. In our study we analyze 25 samples derived from HNSCC patients. 18 samples were HPV-/p16- and 7 HPV+/p16+. We compared the HPV-/p16- versus the HPV+/p16+ and identified differentially expressed RNAs with a fold change greater than 1.5 or less than -1.5. These data were used to obtain 98 genes that are differentially expressed in absence of HPV. The present study offers information regarding clinical and molecular characteristics of HNSCC, both associated and unassociated with HPV, in Mexican patients.
Project description:PTPRD is a tumor suppressor of glioma that is frequently co-deleted with CDKN2A/p16. We show that Ptprd and p16 cooperate to promote gliomagenesis in the RCAS PDGFB / Nestin tv-A glioma mouse model. We found unique gene expression changes within tumor cells of Ptprd+/-p16-/- vs. Ptprd+/+p16-/- and Ptprd-/-p16-/- tumor cells.
Project description:Oncogenic STAT3 functions are known in various malignancies. We found that STAT3 plays an unexpected tumor suppressive role in KRAS-mutant non-small-cell-lung cancer (NSCLC). In mice, tissue-specific inactivation of Stat3 resulted in increased Kras (G12D)-driven NSCLC initiation and malignant progression leading to markedly reduced survival. Clinically, low STAT3 expression levels correlate with poor survival in human lung adenocarcinoma patients with smoking history. Consistently, KRAS-mutant lung tumors showed reduced STAT3 levels. Mechanistically, we show that STAT3 controls NFκB-induced IL-8-expression by sequestering NFκB in the cytoplasm while IL-8 in turn regulates myeloid tumor infiltration and tumor vascularization thereby promoting tumor progression. These results identify a novel STAT3-NFκB-IL-8 axis in KRAS-mutant NSCLC with therapeutic and prognostic relevance WT: Control lung; KRAS: Lung tumors expressing KRAS G12D; KRAS STAT3 KO: Lung tumors expressing KRAS G12D- STAT3 deficient; tumors of four mice pooled per sample
Project description:Transcriptional profiling of p16-induced senescent human diploid fibroblasts compared with proliferating cells. TIG-3 ER-p16 cells (primary normal human diploid fibroblasts expressing a 4-hydroxytamoxifen(4-OHT) regulatable form of human p16) were cultured for 7 days with or without 4-OHT. Total RNA was isolated using TRIzol reagent and were analyzed using the hum