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 Overexpression of BUB1B, CCNA2, CDC20, and CDK1 in tumor tissues predicts poor survival in pancreatic ductal adenocarcinoma

2019 ◽  
Vol 39 (2) ◽  
Author(s):  
Shu Dong ◽  
Fei Huang ◽  
Hao Zhang ◽  
Qiwen Chen
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Tumor Development ◽  
Disease Free Survival ◽  
Tumor Stage ◽  
Gene Expression Omnibus ◽  
Ductal Adenocarcinoma ◽  
Advanced Tumor Stage ◽  
Kaplan Meier ◽  
Advanced Tumor ◽  
Tumor Tissues

AbstractOverexpressed genes in tumors usually contributed to aggressiveness in pancreatic ductal adenocarcinoma (PDAC). Using Gene Expression Omnibus (GEO) profiles including GSE46234, GSE71989, and GSE107610, we detected overexpressed genes in tumors with R program, which were enriched by Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene ontology (GO), and Reactome pathway databases. Then, we performed a survival analysis of enriched genes based on TCGA profile. Our results revealed that high BUB1B, CCNA2, CDC20, and CDK1 expression in tumors was significantly associated with worse overall survival (OS) (Log rank P=0.00338, P=0.0447, P=0.00965, and P=0.00479, respectively), which was validated using a Kaplan–Meier plotter with a median cutoff (Log rank P=0.028, P=0.0035, P=0.039, and P=0.0033, respectively). Moreover, overexpression of BUB1B, CCNA2, CDC20, and CDK1 in tumor tissues was significantly associated with disease-free survival (DFS) in PDAC patients (Log rank P=0.00565, P=0.0357, P=0.00104, and P=0.00121, respectively). BUB1B, CCNA2, CDC20, and CDK1 were significantly overexpressed in deceased PDAC patients (all P<0.01) and in patients with recurrence/disease progression (all P<0.05). In addition, PDAC patients with neoplasms of histologic grade G3-4 had significantly higher BUB1B, CCNA2 and CDC20 levels (all P<0.05). In conclusion, the up-regulation of BUB1B, CCNA2, CDC20, CDK1, and WEE1 in tumor tissues are associated with worse OS and DFS in PDAC and is correlated with advanced tumor stage and tumor development.

ΔTAp73 Upregulation Correlates With Poor Prognosis in Human Tumors: Putative In Vivo Network Involving p73 Isoforms, p53, and E2F-1

2006 ◽  
Vol 24 (5) ◽  
pp. 805-815 ◽  
Author(s):  
Gemma Domínguez ◽  
José M. García ◽  
Cristina Peña ◽  
Javier Silva ◽  
Vanesa García ◽  
...  
Keyword(s):  
Poor Prognosis ◽  
Cell Transformation ◽  
Tumor Stage ◽  
Advanced Tumor Stage ◽  
Breast Cancer Patients ◽  
Oncogenic Ras ◽  
Advanced Tumor ◽  
Tumor Tissues ◽  
Ras Status

Purpose Although full-length TAp73 variants largely mimic p53 suppressor activities, the transactivation-deficient transcripts ΔTAp73 exert an oncogenic effect by inactivating p53 and TAp73 suppressor properties. Additionally, ΔTAp73 may cooperate with oncogenic RAS to induce cell transformation, confer drug resistance, and induce the phosphorylation of phosphorylated Rb. Here, we study the expression of TAp73 and ΔTAp73 variants and assess possible associations with E2F-1, p53 and K-ras status. We address the possible clinical relevance of alterations in these genes. Patients and Methods We determine in 113 colon and 60 breast cancer patients (a) the expression levels of TAp73, ΔTAp73 (ΔEx2p73, ΔEx2/3p73, and ΔNp73), and E2F-1 transcripts by quantitative real-time reverse transcriptase polymerase chain reaction (PCR); (b) mutations in the first exon of K-ras by PCR–single-stranded confirmational polymorphism; and (c) p53 status by immunohistochemistry. Tumor characteristics were examined in each patient. Results Both suppressor and oncogenic isoforms of TP73 were significantly coupregulated in tumor tissues. Associations were observed between (a) p53 wild type status and upregulation of some TP73 variants; (b) overexpression of E2F-1 and some TP73 forms; and (c) upregulation of ΔTAp73 variants and advanced pathologic stage, lymph node metastasis, vascular invasion, presence of polyps, and tumor localization. Conclusion Overexpression of TP73 variants in tumor tissues indicates that they may be involved in colon and breast carcinogenesis. The association between upregulation of ΔTAp73 isoforms and poor prognosis features, specifically advanced tumor stage, suggests that they may be of practical clinical prognostic value. Interestingly, the in vivo associations identified here may indicate a functional network involving p73 variants, p53, and E2F-1.

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 Genetic Variants of lncRNA GAS5 Are Associated with the Clinicopathologic Development of Oral Cancer

2021 ◽  
Vol 11 (5) ◽  
pp. 348
Author(s):  
Ming-Hong Hsieh ◽  
Hsueh-Ju Lu ◽  
Chiao-Wen Lin ◽  
Chia-Yi Lee ◽  
Shang-Jung Yang ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Oral Cancer ◽  
Cancer Patients ◽  
Alcohol Drinking ◽  
Tumor Size ◽  
Genetic Variants ◽  
Tumor Stage ◽  
Advanced Tumor Stage ◽  
Advanced Tumor ◽  
Oral Cancer Patients

The long noncoding RNA, Growth arrest-specific 5 (GAS5) plays a crucial role in the development of oral cancer. However, potential genetic variants in GAS5 that affect the susceptibility and progression of oral cancer have rarely been explored. In this study, two loci of GAS5 single nucleotide polymorphisms (SNPs) (rs145204276 and rs55829688) were genotyped by using the TaqMan allelic discrimination in 1125 oral cancer patients and 1195 non-oral-cancer individuals. After statistical analyses, the distribution of both the GAS5 SNP rs145204276 and GAS5 SNP rs55829688 frequencies were similar between the study and control groups. However, the patients with GAS5 SNP rs145204276 variants (Ins/Del or Del/Del) showed a higher tendency of moderate to poor cell differentiation of oral cancer (OR: 1.454, 95% CI: 1.041–2.031, p = 0.028). Moreover, the GAS5 SNP rs145204276 variants (Ins/Del or Del/Del) in the non-alcohol-drinking population were associated with significantly advanced tumor stage (OR: 1.500, 95% CI: 1.081–2.081, p = 0.015) and larger tumor size (OR: 1.494, 95% CI: 1.076–2.074, p = 0.016). Furthermore, individuals with the GAS5 SNP rs145204276 variant were associated with a higher expression of GAS5 in the GTEx database (p = 0.002), and the higher GAS5 level was associated with poor cell differentiation, advanced tumor stage and larger tumor size in head and neck squamous cell carcinoma from the TCGA database (all p < 0.05). In conclusion, the GAS5 SNP rs145204276 variant is related to poor-differentiation cell status in oral cancer. Besides, the presence of the GAS5 SNP rs145204276 variant is associated with a worse tumor stage and tumor size in oral cancer patients without alcohol drinking.

scholarly journals EPDR1 is related to stages and metastasize in bladder cancer and can be used as a prognostic biomarker

BMC Urology ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yue Yang ◽  
Hanchao Zhang ◽  
Zhengdao Liu ◽  
Faliang Zhao ◽  
Guobiao Liang
Keyword(s):  
Bladder Cancer ◽  
T Cells ◽  
Prognostic Biomarker ◽  
Transmembrane Protein ◽  
Tumor Stage ◽  
Receptor Interaction ◽  
Advanced Tumor Stage ◽  
Normal Bladder ◽  
Advanced Tumor ◽  
Significant Difference

AbstractBackgroundBladder cancer (BLCA) is a malignant urothelial carcinoma and has a high mortality rate. EPDR1 (ependymin related 1) is a type II transmembrane protein and related to calcium-dependent cell adhesion.MethodsWe explored the potential oncogenic roles of EPDR1 in BLCA basing on the multiple public datasets.ResultsWe found that EPDR1 expression had a significant difference in BLCA and adjacent normal bladder tissues, and the level of EPDR1was up-regulated with advanced tumor stage and metastasis in BLCA. Meanwhile, the high expression group of EPDR1 had a shorter OS compared to the low or medium expression-group. Furthermore, EPDR1 expression was associated with tumor-infiltrating immune cells (TIICs), including NK cells, CD8 + T cells, CD4 + T cells, Macrophages cells, and so on. Moreover, EPDR1 also involved in several signaling pathways as well as PI3K/AKT pathway, Cytokine receptor interaction, and apoptosis.ConclusionEPDR1 can be used as a novel prognostic biomarker as well as an effective target for diagnosis and treatment in BLCA.

scholarly journals E-Cadherin expression in human tumors: a tissue microarray study on 10,851 tumors

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Eike Burandt ◽  
Felix Lübbersmeyer ◽  
Natalia Gorbokon ◽  
Franziska Büscheck ◽  
Andreas M. Luebke ◽  
...  
Keyword(s):  
Tissue Microarray ◽  
Poor Prognosis ◽  
Triple Negative ◽  
Lobular Carcinoma ◽  
Tumor Stage ◽  
Advanced Tumor Stage ◽  
Carcinoma Of The Breast ◽  
Advanced Tumor ◽  
Tumor Entities ◽  
E Cadherin

Abstract Background The E-Cadherin gene (CDH1, Cadherin 1), located at 16q22.1 encodes for a calcium-dependent membranous glycoprotein with an important role in cellular adhesion and polarity maintenance. Methods To systematically determine E-Cadherin protein expression in normal and cancerous tissues, 14,637 tumor samples from 112 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types were analyzed by immunohistochemistry in a tissue microarray format. Results E-Cadherin was strongly expressed in normal epithelial cells of most organs. From 77 tumor entities derived from cell types normally positive for E-Cadherin, 35 (45.5%) retained at least a weak E-Cadherin immunostaining in ≥99% of cases and 61 (79.2%) in ≥90% of cases. Tumors with the highest rates of E-Cadherin loss included Merkel cell carcinoma, anaplastic thyroid carcinoma, lobular carcinoma of the breast, and sarcomatoid and small cell neuroendocrine carcinomas of the urinary bladder. Reduced E-Cadherin expression was linked to higher grade (p = 0.0009), triple negative receptor status (p = 0.0336), and poor prognosis (p = 0.0466) in invasive breast carcinoma of no special type, triple negative receptor status in lobular carcinoma of the breast (p = 0.0454), advanced pT stage (p = 0.0047) and lymph node metastasis in colorectal cancer (p < 0.0001), and was more common in recurrent than in primary prostate cancer (p < 0.0001). Of 29 tumor entities derived from E-Cadherin negative normal tissues, a weak to strong E-Cadherin staining could be detected in at least 10% of cases in 15 different tumor entities (51.7%). Tumors with the highest frequency of E-Cadherin upregulation included various subtypes of testicular germ cell tumors and renal cell carcinomas (RCC). E-Cadherin upregulation was more commonly seen in malignant than in benign soft tissue tumors (p = 0.0104) and was associated with advanced tumor stage (p = 0.0276) and higher grade (p = 0.0035) in clear cell RCC, and linked to advanced tumor stage (p = 0.0424) and poor prognosis in papillary RCC (p ≤ 0.05). Conclusion E-Cadherin is consistently expressed in various epithelial cancers. Down-regulation or loss of E-Cadherin expression in cancers arising from E-Cadherin positive tissues as well as E-Cadherin neo-expression in cancers arising from E-Cadherin negative tissues is linked to cancer progression and may reflect tumor dedifferentiation.

scholarly journals Type III TGF-β Receptor Down-Regulation Promoted Tumor Progression via Complement Component C5a Induction in Hepatocellular Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1503
Author(s):  
Oscar Wai Ho Yeung ◽  
Xiang Qi ◽  
Li Pang ◽  
Hui Liu ◽  
Kevin Tak Pan Ng ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Progression ◽  
Tumor Stage ◽  
Complement Component ◽  
Soluble Form ◽  
Advanced Tumor Stage ◽  
Down Regulation ◽  
Type Iii ◽  
Advanced Tumor ◽  
Β Receptor

Background and Aims—Transforming growth factor-beta (TGF-β) signaling orchestrates tumorigenesis and one of the family members, TGF-β receptor type III (TGFβR3), are distinctively under-expressed in numerous malignancies. Currently, the clinical impact of TGFβR3 down-regulation and the underlying mechanism remains unclear in hepatocellular carcinoma (HCC). Here, we aimed to identify the tumor-promoting roles of decreased TGFβR3 expression in HCC progression. Materials and Methods—For clinical analysis, plasma and liver specimens were collected from 100 HCC patients who underwent curative resection for the quantification of TGFβR3 by q-PCR and ELISA. To study the tumor-promoting mechanism of TGFβR3 downregulation, HCC mouse models and TGFβR3 knockout cell lines were applied. Results—Significant downregulation of TGFβR3 and its soluble form (sTGFβR3) were found in HCC tissues and plasma compared to healthy individuals (p < 0.01). Patients with <9.4 ng/mL sTGFβR3 exhibited advanced tumor stage, higher recurrence rate and shorter disease-free survival (p < 0.05). The tumor-suppressive function of sTGFβR3 was further revealed in an orthotopic mouse HCC model, resulting in 2-fold tumor volume reduction. In TGFβR3 knockout hepatocyte and HCC cells, increased complement component C5a was observed and strongly correlated with shorter survival and advanced tumor stage (p < 0.01). Interestingly, C5a activated the tumor-promoting Th-17 response in tumor associated macrophages. Conclusion—TGFβR3 suppressed tumor progression, and decreased expression resulted in poor prognosis in HCC patients through upregulation of tumor-promoting complement C5a.

scholarly journals Larinksin Skuamöz Hücreli Karsinomunda LGALS3 Gen Varyasyonlarıyla Histopatolojik Kriterler Arasında Bir İlişki Var Mı ?

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Cem Horozoglu ◽  
Seyda Demirkol ◽  
Aysegul Verim ◽  
Dilara Sonmez ◽  
Saime Sürmen ◽  
...  
Keyword(s):  
Positive Family History ◽  
Treatment Resistance ◽  
Tumor Stage ◽  
Dynamic Factor ◽  
Solid Organ ◽  
Advanced Tumor Stage ◽  
Multiple Tumor ◽  
Advanced Tumor ◽  
Galectin 3 ◽  
Statistical Relationships

Abstract Objectives Genetic variations of LGALS3 (Galectin-3) were found to be associated with treatment resistance, mortality, recurrence, high tumor volume and multiple tumor involvement in solid organ cancers. The modulators of extracellular matrix (ECM), which is a dynamic factor in the larynx tissue with high biomechanical and regenerating ability, can play an important role. We aimed to investigate the relationship between the genetic variants of LGALS3, one of these modulators, with Laryngeal Squamous Cell Carcinoma (LSCC). Methods LGALS3 gene variations were genotyped by PCR-RFLP method using genomic DNA samples obtained from peripheral blood samples of 74 patients diagnosed with LSCC and 94 healthy controls. Results The C allele carriage for the Rs4652 genetic variant was found to be higher (p=0.017) in patients with LSCC. Statistical relationships were found between homozygous genotypes of this variant (CC/AA) with advanced tumor stage (p=0.017) and presence of reflux (p=0.036). CC genotype for rs4644 was found to be higher in cases with positive family history (p=0.036). Conclusions Our findings of LGALS3 gene variants, which are also found to be associated with other solid cancers, suggest that they may play a role in LSCC pathophysiology similarly.

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