Correction: TAZ Expression as a Prognostic Indicator in Colorectal Cancer.
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ABSTRACT:
SUBMITTER: Yuen HF
PROVIDER: S-EPMC8031417 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The Hippo pathway restricts the activity of transcriptional coactivators TAZ (WWTR1) and YAP. TAZ and YAP are reported to be overexpressed in various cancers, however, their prognostic significance in colorectal cancers remains unstudied. The expression levels of TAZ and YAP, and their downstream transcriptional targets, AXL and CTGF, were extracted from two independent colon cancer patient datasets available in the Gene Expression Omnibus database, totaling 522 patients. We found that mRNA expressions of both TAZ and YAP were positively correlated with those of AXL and CTGF (p<0.05). High level mRNA expression of TAZ, AXL or CTGF significantly correlated with shorter survival. Importantly, patients co-overexpressing all 3 genes had a significantly shorter survival time, and combinatorial expression of these 3 genes was an independent predictor for survival. The downstream target genes for TAZ-AXL-CTGF overexpression were identified by Java application MyStats. Interestingly, genes that are associated with colon cancer progression (ANTXR1, EFEMP2, SULF1, TAGLN, VCAN, ZEB1 and ZEB2) were upregulated in patients co-overexpressing TAZ-AXL-CTGF. This TAZ-AXL-CTGF gene expression signature (GES) was then applied to Connectivity Map to identify small molecules that could potentially be utilized to reverse this GES. Of the top 20 small molecules identified by connectivity map, amiloride (a potassium sparing diuretic), and tretinoin (all-trans retinoic acid) have shown therapeutic promise in inhibition of colon cancer cell growth. Using MyStats, we found that low level expression of either ANO1 or SQLE were associated with a better prognosis in patients who co-overexpressed TAZ-AXL-CTGF, and that ANO1 was an independent predictor of survival together with TAZ-AXL-CTGF. Finally, we confirmed that TAZ regulates Axl, and plays an important role in clonogenicity and non-adherent growth in vitro and tumor formation in vivo. These data suggest that TAZ could be a therapeutic target for the treatment of colon cancer.
| S-EPMC3553150 | biostudies-literature
Project description:AimTo determine if TSPAN1 overexpression is associated with clinicopathological and prognostic factors in human colorectal adenocarcinoma.MethodsTotal RNA was extracted in 20 human adenocarcinoma tissues for TSPAN1 mRNA assay by RT-PCR. Eighty-eight specimens of human colorectal adenocarcinoma were surgically removed. TSPAN1 protein levels in cancer tissues were determined by immunohistochemistry using a polyclonal antibody against self-prepared TSPAN1. The correlation between TSPAN1 expression and the clinicopathological factors and the overall survival rate was analyzed by univariate and multivariate assay.ResultsTSPAN1 mRNA was detected in 90.0% (18/20) of cancerous tissues. The light density of TSPAN1 mRNA expression levels was 0.89 +/- 0.30 in adenocarcinoma by gel-image system. TSPAN1 protein expression was detected in 78.41% (69/88) and weakly expressed in 40% normal colorectal tissues. There were significant differences between colorectal adenocarcinoma and normal control epithelium (P < 0.05). TSPAN1 protein expression in colorectal cancerous tissue was significantly correlated with the histological grade, cell expression PCNA, lymph nodal metastasis and TNM staging of the disease. Patients with TSPAN1 protein overexpression had a significantly shorter survival period than that in patients with TSPAN1 protein negative or weak expression, respectively (P < 0.05). Furthermore, by multivariate analysis, TSPAN1 protein expression demonstrated an independent prognostic factor for human colorectal cancers (P < 0.05, relative risk 0.755; 95% confidence interval 0.302-1.208).ConclusionThe expression of TSPAN1 gene is increased in colorectal carcinoma, suggesting that TSPAN1 might serve as an independent prognostic factor for the colorectal adenocarcinoma patients.
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Project description:Studies have shown that LIM domain kinase 1 (LIMK1) is upregulated in a variety of tumors and may be a potential detection target. The present study analyzed the expression difference of LIMK1 and its relationship with tumor clinicopathological characteristics and tumor microenvironment in colorectal cancer (CRC). The transcriptomic data of LIMK1 with CRC were downloaded from The Cancer Genome Atlas (TCGA) database and GEO databases for analyzing the expression of LIMK1 mRNA and the correlation with the prognosis of patients. The protein expression of LIMK1 was obtained from the Human Protein Atlas. The receiver operating characteristic (ROC) curve and Kaplan-Meier was used to evaluate the expression characteristics and prognostic differences of LIMK1 in CRC. STRING was used to analyze co-expression genes of LIMK1. The tumor immune estimation resource was applied to the correlation between LIMK1 expression and immune infiltrates. The present study verified LIMK1 expression at the level of clinical samples collected from the Tianjin Medical University General Hospital and cell lines using reverse transcription-quantitative PCR. The mRNA and protein expression of LIMK1 were both upregulated in tumor tissues compared with adjacent tissues in CRC. The expression levels of LIMK1 were positively associated with clinical-pathological features of CRC including lymphatic invasion (P=4.00×10−2) and high pathologic stages (P=4.20×10−2). The AUC value of LIMK1 in CRC was 0.937 (95% CI: 0.918-0.957) through ROC analysis. Under the best cut-off value (4.009), the sensitivity and specificity were 98 and 81.9%. LIMK1 expression was mainly related to CD4+ T cells, macrophages and dendritic cells in the immune microenvironment of CRC. In conclusion, the high expression of LIMK1 in CRC was closely related to the clinical features and prognosis of patients. Therefore, LIMK1 was a promising prognostic indicator and a potential target for immunotherapy in CRC.
| S-EPMC9185146 | biostudies-literature
Project description:Particularly interesting new cysteine-histidine-rich protein (PINCH), a LIM domain adapter protein that functions in the integrin and growth factor signal transduction pathway, is upregulated in stroma associated with many common cancers. The finding suggested that PINCH may be involved in promoting tumor-stromal interactions that support tumor progression, and, if so, tumors with abundant PINCH stromal staining may have a worse prognosis. To test this hypothesis, 174 primary colorectal adenocarcinomas with 39 distant normal mucosa samples and 26 metastases in the lymph nodes were studied by immunohistochemistry, and 7 additional colon tumors were studied by Western blot analysis and immunofluorescence. The abundance of PINCH protein in stroma increased from normal mucosa to primary tumor to metastasis (P <.05), and was more intense at the invasive margin than it was in the intratumoral stroma. Strong stromal immunostaining for PINCH was shown to predict a worse outcome (rate ratio 2.1, 95% CI 1.16-3.37, P=.01), independent of Dukes stage, growth pattern, and tumor differentiation. PINCH was detected in fibroblasts, myofibroblasts, and a proportion of endothelial cells of the tumor vasculature, supporting the involvement of PINCH in promoting tumor-stromal interactions that support tumor progression. Interestingly, stromal staining for PINCH was an independent prognostic indicator in colorectal cancer.
| S-EPMC1531683 | biostudies-literature
Project description:BackgroundTumor microenvironment has recently drawn attention in that it is related with tumor prognosis. Cancer-associated fibroblast also plays a critical role in cancer invasiveness and progression in colorectal cancers. Periostin (POSTN), originally identified to be expressed in osteoblasts and osteoblast-derived cells, is expressed in cancer-associated fibroblasts in several tissue types of cancer. Recent studies suggest an association between stromal overexpression of POSTN and poor prognosis of cancer patients.MethodsWe analyzed colorectal cancer cases for their expression status of POSTN in tumor stroma using immunohistochemistry and correlated the expression status with clinicopathological and molecular features.ResultsHigh level of POSTN expression in tumor stroma was closely associated with tumor location in proximal colon, infiltrative growth pattern, undifferentiated histology, tumor budding, luminal necrosis, and higher TNM stage. High expression status of POSTN in tumor stroma was found to be an independent prognostic parameter implicating poor 5-year cancer-specific survival and 5-year progression-free survival.ConclusionsOur findings suggest that POSTN overexpression in tumor stroma of colorectal cancers could be a possible candidate marker for predicting poor prognosis in patients with colorectal cancers.
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Project description:Osteopontin (OPN) has been shown to promote colorectal cancer (CRC) progression; however, the mechanism of OPN-induced CRC progression is largely unknown. In this study, we found that OPN overexpression led to enhanced anchorage-independent growth, cell migration and invasion in KRAS gene mutant cells but to a lesser extent in KRAS wild-type cells. OPN overexpression also induced PI3K signalling, expression of Snail and Matrix metallopeptidase 9 (MMP9), and suppressed the expression of E-cadherin in KRAS mutant cells. In human CRC specimens, a high-level expression of OPN significantly predicted poorer survival in CRC patients and OPN expression was positively correlated with MMP9 expression, and negatively correlated with E-cadherin expression. Furthermore, we have found that 15 genes were co-upregulated in OPN highly expression CRC and a list of candidate drugs that may have potential to reverse the secreted phosphoprotein 1 (SPP1) gene signature by connectivity mapping. In summary, OPN is a potential prognostic indicator and therapeutic target for colon cancer.
| S-EPMC6111822 | biostudies-literature
Project description:Genetically abnormal fibroblasts are notably more prevalent in colorectal cancer (CRC) than in adjacent normal tissue, emphasizing their significance in driving the heterogeneity of the tumor microenvironment. Functioning as a significant regulatory gene in the context of fibrosis, FOXF1 adjacent non-coding developmental regulatory RNA (FENDRR) has exhibited abnormal expression in colorectal cancer and interstitial localization in our experiments. However, current research on the role of FENDRR in cancer has focused solely on its impact on cancer cells. Its crucial role in the tumor stroma is yet to be explored. The goal of this study was to understand the relationship between atypical FENDRR expression, its distinct localization, and genetically abnormal fibroblasts in CRC. We aimed to establish the function of FENDRR within the stromal compartment of patients through bioinformatics. Our study confirmed that FENDRR suppresses cancer-associated fibroblasts by inhibiting their activation and collagen generation in CRC. Furthermore, our findings suggest that low FENDRR expression indicates a poor prognosis. Therefore, we propose that FENDRR is a promising therapeutic target for future studies in CRC.
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Project description:Background:Serine/arginine protein kinase 1 (SRPK1) is a protein kinase that belongs to the serine/arginine-rich domain family of splicing factors which are essential for splice-site selection, especially the modulation for RNA metabolism, localization, and translation. High expression of SRPK1 has been found in numerous human cancers, but its mechanism in colorectal cancer (CRC) is still rarely reported. Purpose:To investigate the expression of SRPK1 in CRC tissues and cells and determine its functions and mechanism in CRC. Methods:The expression of SRPK1 was explored in human CRC patients and cells by immunohistochemistry, real-time quantitative PCR, and Western blot; Cell Counting Kit-8, Transwell, flow cytometry, and tube formation assay were used to investigate the CRC cell viability, migration, apoptosis, and angiogenesis, respectively. Results:SRPK1 was overexpressed in CRC tumor tissues and cells, and correlated with tumor node metastasis stage; inhibition of SRPK1 by siRNA resulted in decreased cell growth and migration, significantly increased apoptosis, and suppressed angiogenesis. Conclusion:SRPK1 can be a prognostic indicator of CRC and may be a therapeutic target for CRC.
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Project description:Background:Metabolic reprogramming in cancer encompasses the insulin receptor (IR) as a player of energy homeostasis and proliferation. We aimed to characterize vascular (VIR) and epithelial (EIR) IR expression in CRC and correlate it with clinico-pathological parameters and survival. Methods:1580 primary CRCs were explored by immunohistochemistry for evaluation of VIR and EIR. Subgroup analyses included in situ hybridization for IR isoform A (IR-A) and DNA mismatch repair protein immunohistochemistry. Clinico-pathological and survival parameters were studied. Results:High VIR was evident in 63.5% of all CRC samples and was associated with T-stage (P = 0.005). EIR was present in 72.2% and was associated with lower T-stages (P = 0.006) and UICC-stages (P < 0.001). EIR negativity was associated with increased metastasis (P = 0.028), nodal spread (P < 0.001), lymphatic invasion (P = 0.008) and a decreased tumor-specific (P = 0.011) and overall survival (P = 0.007; 95%-C.I.: 44.5-84.1). EIR negativity in UICC-stage II was associated with a significantly worse tumor-specific (P = 0.045) and overall (P = 0.043) survival. IR-A was expressed in CRC vessels and cells. Conclusions:We demonstrate VIR to be frequent in CRC and characterize EIR negativity as an important prognostic risk factor. The association between EIR negativity and worse survival in UICC-stage II should be prospectively evaluated for an application in therapeutic algorithms.
| S-EPMC6331016 | biostudies-literature
Project description:Colorectal cancer (CRC) is the third most common cancer in males and the second in females worldwide with very poor prognosis. Collagen alpha-1(III) (COL3A1) gene, encoding an extracellular matrix protein, is upregulated in human cancers. Here, we revealed that COL3A1 was increased in CRC by analysis of five Oncomine gene expression datasets (n = 496). Immunohistochemistry analysis of a tissue microarray (n = 90) demonstrated that cancer epithelial but not stromal COL3A1 was significantly upregulated comparing with the normal counterparts. High COL3A1 mRNA and/or protein expression was accompanied with high stage, T stage, Dukes stage, grade and older age, as well as smoking and recurrence status. Upregulated COL3A1 predicted poor overall (p = 0.003) and disease-free (p = 0.025) survival. Increased epithelial but not stromal COL3A1 protein predicted worse outcome (p = 0.03). Older patients (age>65) with high COL3A1 had worse survival than younger (age?65) with high COL3A1. Plasma COL3A1 was increased in CRC patients (n = 86) by 5.4 fold comparing with healthy individuals, enteritis and polyps patients. Plasma COL3A1 had an area under curve (AUC) of 0.92 and the best sensitivity/specificity of 98.8%/69.1%. While plasma CEA had a poorer prediction power (AUC = 0.791, sensitivity/selectivity = 70.2%/73.0%). Older patients (age?60) had higher plasma COL3A1 than younger patients. The epithelial COL3A1 protein had an AUC of 0.975 and the best sensitivity/specificity of 95.2%/91.1%. Silencing of COL3A1 suppressed CRC cell proliferation in in vitro MTT assay and in in vivo Zebra fish xenograft model by downregulation of PI3K/AKT and WNT signaling. COL3A1 was a novel diagnosis and prognosis marker of CRC.
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