scholarly journals Cytoplasm localized ARID1B promotes oncogenesis in pancreatic cancer by activating RAF-ERK signaling

2019 ◽  
Author(s):  
Srinivas Animireddy ◽  
Padmavathi Kavadipula ◽  
Viswakalyan Kotapalli ◽  
Swarnalata Gowrishankar ◽  
Satish Rao ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Nuclear Localization ◽  
Erk Signaling ◽  
Cancer Tissue ◽  
Advanced Tumor Stage ◽  
Cytoplasmic Localization ◽  
Reporter Protein ◽  
Cell Growth And Migration ◽  
Pancreatic Cancer Cells ◽  
Advanced Tumor

AbstractThe ARID1B/BAF250b subunit of the human SWI/SNF chromatin remodeling complex is a canonical nuclear tumor suppressor. Immunohistochemistry on a pancreatic cancer tissue microarray revealed significant ARID1B cytoplasmic localization that correlated with advanced tumor stage and lymph node positivity. Identification of the nuclear localization signal (NLS) using in silico prediction and subcellular localization studies facilitated evaluation of a possible cytoplasmic function for ARID1B. A cytoplasm-restricted ARID1B-NLS mutant was significantly compromised to regulate transcription activation and tumor suppression functions, as expected. Surprisingly however, cytoplasm-localized ARID1B could bind c-RAF and PPP1CA causing stimulation of RAS-RAF-ERK signaling and β-catenin transcription activity in pancreatic cancer cells. More importantly, cytoplasmic ARID1B resulted in an induction of cell growth and migration in pancreatic cancer cell lines that was dependent on ERK signaling and caused increased tumorigenesis in nude mice. NLS peptides representing mutations identified from pancreatic cancer samples exhibiting ARID1B cytoplasmic localization or curated from cancer somatic mutation database were significantly compromised to effect nuclear localization of a reporter protein. ARID1B cytoplasmic localization correlated significantly with active forms of ERK and β-catenin in primary pancreatic tumor samples. ARID1B may therefore promote oncogenesis through non-canonical cytoplasm-based gain of function mechanisms in addition to dysregulation in the nucleus.

scholarly journals Aberrant cytoplasmic localization of ARID1B activates ERK signaling and promotes oncogenesis

2020 ◽  
pp. jcs.251637
Author(s):  
Srinivas Animireddy ◽  
Padmavathi Kavadipula ◽  
Viswakalyan Kotapalli ◽  
Swarnalata Gowrishankar ◽  
Satish Rao ◽  
...  
Keyword(s):  
Pancreatic Tumor ◽  
Tumor Stage ◽  
Erk Signaling ◽  
Advanced Tumor Stage ◽  
Cytoplasmic Localization ◽  
Advanced Tumor ◽  
Tumor Tissues ◽  
Localization Signal ◽  
Intracellular Fluorescence ◽  
Oncogenic Function

The ARID1B/BAF250b subunit of the human SWI/SNF chromatin remodeling complex is a canonical nuclear tumor suppressor. We employed in silico prediction, intracellular fluorescence and cellular fractionation based subcellular localization analyses to identify the ARID1B nuclear localization signal. A cytoplasm-restricted ARID1B-NLS mutant was significantly compromised in its canonical transcription activation and tumor suppressive functions, as expected. Surprisingly however, cytoplasmic localization appeared to induce a gain of oncogenic function in ARID1B as evidenced from several cell line and mouse xenograft based assays. Mechanistically, cytoplasm-localized ARID1B could bind c-RAF and PPP1CA causing stimulation of RAF-ERK signaling and β-catenin transcription activity. ARID1B harboring NLS mutations derived from tumor samples also exhibited aberrant cytoplasmic localization and acquired a neo-morphic oncogenic function via activation of RAF-ERK signaling. Further, immunohistochemistry on a tissue microarray revealed significant correlation of ARID1B cytoplasmic localization with increased levels of active forms of ERK1/2 and β-catenin as well as with advanced tumor stage and lymph node positivity in human primary pancreatic tumor tissues. ARID1B therefore promotes oncogenesis through cytoplasm-based gain of function mechanisms in addition to dysregulation in the nucleus.

scholarly journals YOD1 Serves as a Potential Prognostic Biomarker For Pancreatic Cancer

2021 ◽  
Author(s):  
Zhishuo Zhang ◽  
Wenxia Zhao ◽  
Yiming Li ◽  
Yang Li ◽  
Yang Liu ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Enrichment Analysis ◽  
Functional Enrichment ◽  
Expression Level ◽  
Human Pancreatic Cancer ◽  
Cancer Tissue ◽  
Post Translational Modification ◽  
Pancreatic Cancer Cells ◽  
Proliferation And Metastasis ◽  
Cancer Tissues

Abstract Background Ubiquitination is a basic post-translational modification of intracellular proteins and can be reversed enzymatically by DUBs (deubiquitinating enzymes). More than 90 DUBs have been identified. Among them, the deubiquitinating enzyme YOD1, a member of the ovarian tumor domain protease (OTUs) subfamily, is involved in the regulation of endoplasmic reticulum (ER)-related degradation pathways. In fact, it is reported that YOD1 is an important proliferation and metastasis-inducing gene, which can stimulate the characteristics of cancer stem cells and maintain circulating tumor cells (CTC). However, the expression level, prognostic effect, biological function and mechanism of YOD1 in pancreatic cancer are still unclear. ResultsIn the GEO and TCGA databases, YOD1 mRNA expression is significantly up-regulated in a variety of human pancreatic cancer tissues. Survival analysis showed that the up-regulation of YOD1 can predict poor prognosis of pancreatic cancer. Cox analysis showed that high YOD1 expression is an independent prognostic factor of pancreatic cancer. ROC analysis shows that YOD1 has significant diagnostic value. The immunohistochemistry (IHC) results showed that the protein expression level of YOD1 in pancreatic cancer tissue was higher than that in neighboring non-pancreatic cancer tissues (P<0.001). In addition, we found that YOD1 expression is negatively correlated with the infiltration level of CD8+ T cells, macrophages, neutrophils and dendritic cells (DC) in pancreatic cancer. The expression of YOD1 has a strong correlation with the different immune marker sets in PAAD. Co-expression network and functional enrichment analysis indicate that YOD1 may participate in the development of pancreatic cancer through cell adhesion molecules, p53, Hippo, TGF-β and other pathways. The experimental results of EDU, Transwell and Western blot indicate that YOD1 is highly expressed in pancreatic cancer cells and pancreatic cancer tissues, and its overexpression can promote the proliferation and metastasis of pancreatic cancer cells.Conclusion Our results indicate that YOD1 may be a useful biomarker for the prognosis of human pancreatic cancer, and it may also be a potential molecular target for the diagnosis and treatment of pancreatic cancer.

scholarly journals MicroRNA-7 as a Potential Biomarker for Prognosis in Pancreatic Cancer

2020 ◽  
Vol 2020 ◽  
pp. 1-13 ◽  
Author(s):  
Zhi-qiang Ye ◽  
Chang-lin Zou ◽  
Han-bin Chen ◽  
Ming-jie Jiang ◽  
Zhu Mei ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Progression ◽  
Clinical Significance ◽  
Cancer Progression ◽  
Cox Proportional Hazards Model ◽  
The Cancer Genome Atlas ◽  
Cancer Tissue ◽  
Advanced Tumor ◽  
Potential Biomarker ◽  
Tumor Stages

MicroRNAs play critical roles in tumor progression. Our recent study has indicated that microRNA-7 (miR-7) impairs autophagy-derived pools of glucose to suppress the glycolysis in pancreatic cancer progression. However, the roles of miR-7 in clinical significance and chemoresistance of pancreatic cancer remain unexplored. The aim of this study was to assess the expression of miR-7 in patients with pancreatic cancer and to evaluate the possibility of its usage as a prognostic molecular biomarker. MicroRNA array-based quantification analysis of 372 miRNAs was compared in serum between pancreatic cancer and healthy individuals, gemcitabine-sensitive and gemcitabine-resistance patients. We identified miR-7 showed the potential predictive power for gemcitabine-sensitive patients with pancreatic cancer. Then, the results were validated in pancreatic tissue microarray and The Cancer Genome Atlas (TCGA) dataset, demonstrating that lower miR-7 expression was correlated with more advanced tumor stages and worse prognosis in pancreatic cancer. The Cox proportional-hazards model analysis identified miR-7 to be an independent variable for prediction of the survival. Furthermore, the mechanistic exploration suggested the clinical significance of miR-7 involved its interference effect on autophagy and glycolysis in pancreatic cancer using pancreatic cancer tissue microarrays and TCGA data. Therefore, the results of the present study provide evidences that low microRNA-7 expression may contribute to tumor progression and poor prognosis in pancreatic cancer.

scholarly journals Involvement of MEK–ERK signaling pathway in the inhibition of cell growth by troglitazone in human pancreatic cancer cells

2005 ◽  
Vol 332 (1) ◽  
pp. 89-94 ◽  
Author(s):  
Wataru Motomura ◽  
Satoshi Tanno ◽  
Nobuhiko Takahashi ◽  
Miho Nagamine ◽  
Mitsuko Fukuda ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Growth ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Erk Signaling ◽  
Human Pancreatic Cancer ◽  
Pancreatic Cancer Cells

scholarly journals LncRNA CERS6-AS1 promotes proliferation and metastasis through the upregulation of YWHAG and activation of ERK signaling in pancreatic cancer

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Jian Xu ◽  
Jie Wang ◽  
Zhiwei He ◽  
Peng Chen ◽  
Xueyi Jiang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Proliferation ◽  
Target Genes ◽  
Erk Signaling ◽  
Pcr Analysis ◽  
Cell Growth And Migration ◽  
Mesenchymal Transition ◽  
Potential Biomarker ◽  
Proliferation And Metastasis ◽  
Cell Proliferation And Metastasis

AbstractLncRNAs play essential regulatory roles in pancreatic cancer (PC) tumorigenesis and progression. We aimed to investigate the role of lncRNA CERS6-AS1 in PC. CERS6-AS1 expression was determined in PC tissues and cell lines by PCR analysis. The roles of CERS6-AS1 on proliferation, migration, invasion, and epithelial to mesenchymal transition (EMT) were confirmed via CCK-8 assay, EDU assay, transwell assay, wound healing assay, and western blot assay. Besides, the interaction between CERS6-AS1 and their target genes was verified by luciferase report assays and RIP assays. Animal assays and clinical data analysis were performed to validate the functions in vivo. We found that lncRNA CERS6-AS1 was highly expressed in PC tissues and cells. Additionally, high expression of CERS6-AS1 was obviously associated with poor prognosis. Functional assays demonstrated that CERS6-AS1 downregulation significantly inhibited PC cell growth and migration. Moreover, CERS6-AS1 exerted as a molecular sponge for miR-217-5p (miR-217), and miR-217 was confirmed as a potential target of CERS6-AS1. Subsequently, miR-217 suppressed PC cell proliferation and metastasis by directly targeting YWHAG, which interacted with RAF1 and promoted its phosphorylation, leading to RAF1-mediated ERK signaling activation and translocation of phosphorylated ERK from the cytoplasm to the nucleus. Mechanically, CERS6-AS1 silencing significantly inhibited PC cell proliferation and metastasis via a miR-217/YWHAG/RAF1 signaling axis. CERS6-AS1 exerts as a carcinogen in PC to promote malignant features and behaves as a competitive endogenous RNA for miR-217. We identified CERS6-AS1 as a potential biomarker or therapeutic target to improve PC diagnosis and treatment outcomes.

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