Expression In Carcinoma Tissues Research Articles

ZNF8 promotes progression of gastrointestinal cancers via a p53-dependent mechanism

p53 is a critical tumor suppressor, and the disruption of its normal function is often a prerequisite for the development or progression of tumors. Our previous works revealed that multiple members of Krüppel-associated box (KRAB) domain zinc-finger proteins (KZFPs) family regulate p53 transcriptional activity by interacting with it. But the tumor biology functions of these members have not been fully elucidated. Here, the pan-cancer analysis related to gastrointestinal cancers (GICs) revealed that ZNF8, a p53-interacting protein, is an unfavorable prognostic factor for patients with malignancies. ZNF8 interacts with p53 and further depresses its transcriptional activity in colon cancer cells. The knockdown of ZNF8 or the overexpression of ZNF8 inhibits or facilitates the in vitro colony formation, migration, invasion, and angiogenesis of p53+/+ colon cancer HCT116 cells, HepG2 cells and EC109 cells rather than p53−/− colon cancer HCT116 cells and p53-knockout HepG2 cells, respectively. Xenograft experiments conducted in vivo also showed that the knockdown of ZNF8 in p53+/+ but not in p53−/− HCT116 cells curbs the tumor growth and metastasis to lung, leading to an extended life span for tumor-bearing mice. Clinically, two independent immunohistochemistry cohorts of colon cancer and esophageal cancer also indicated that ZNF8 is higher expression in carcinoma tissues than adjacent tissues and this is associated with worse overall survival outcomes in patients without harboring p53 mutation. Together, our results provide insight into the p53-specific tumor oncogenic function of ZNF8. ZNF8 may prove to be a potential target for GICs treatment.

Effects of miR-32 on Proliferation, Apoptosis, Invasion and Migration of Osteosarcoma Cells by Targeting PTEN

Objective: To observe the impact of miR-32 on the proliferation and apoptosis of osteosarcoma U2OS cell line, and to explore its possible causative roles. Methods: Detection of miR-32 expression in carcinoma tissues and normal adjacent tissues of 44 osteosarcoma patients was achieved employing QRT-PCR technique. The liposome transfection technique was utilized to knock down the miR-32 of osteosarcoma U2OS cells and determine osteosarcoma cell proliferation, apoptosis migration ae well as invasion. Results: MiR-32 expressions in cancer tissues of osteosarcoma patients were markedly higher than that of adjacent tissues. Moreover, miR-32 expression further decreased as the clinical stage of the tumor progressed. MiR-32 knockdown could remarkably inhibit the formation of osteosarcoma cell clones, proliferation,migration and invasion level, whereas promote cancer cell apoptosis. Meanwhile, miR-32 knockdown can noteworthily reduce the level of oxidative stress and autophagy in osteosarcoma cells. Mechanistically, miR-32 can target and inhibit PTEN protein, knocking down miR-32 can activate PTEN/mTOR signaling pathway. In contrast, inhibiting PTEN protein expression can counteract the antitumor effect caused by miR-32 knockdown. Subcutaneous tumorigenesis experiments further confirmed the anti-osteosarcoma cell growth effect of miR-32. Conclusion: MiR-32 expression is apparently increased in cancer tissues of osteosarcoma patients. MiR-32 knockdown can suppress the proliferation of osteosarcoma cells and promote their apoptosis by targeting activation of PTEN-mediated mTOR activation.

Aberrant kinesin family member 2A signifies tumor size and invasion, and may help predict prognosis of patients with papillary thyroid carcinoma.

Kinesin family member 2A (KIF2A) has been reported as an oncogene and potential biomarker for the progression of numerous cancer types; however, its role in papillary thyroid carcinoma (PTC) has remained elusive. The present study aimed to assess KIF2A expression in patients with PTC and explore the potential association between KIF2A, clinicopathological features and the prognosis of PTC. A total of 200 patients with PTC who received surgical resection were retrospectively reviewed. KIF2A expression was detected using immunohistochemistry (IHC) in 200 pairs of carcinoma/para-carcinoma tissues and using reverse transcription-quantitative PCR in 91 pairs of carcinoma/para-carcinoma tissues. Clinical and pathological data, disease-free survival (DFS) and overall survival (OS) rates of all patients were obtained. The results of the present study demonstrated that KIF2A protein and mRNA expression were both elevated in carcinoma tissues compared with those in para-carcinoma tissues. KIF2A protein expression in carcinoma tissues was positively associated with increased tumor size and a higher pathologic tumor-nodes-metastasis (pTNM) stage. However, KIF2A mRNA expression in carcinoma tissues was only associated with an increased pTNM stage and not with any other clinicopathological features. In addition, high levels of KIF2A protein expression in carcinoma tissues led to a poor predicted DFS, but were not associated with OS. Following adjustments using a multivariate Cox regression model, high KIF2A protein expression levels were indicated to be independently associated with a decreased DFS. In conclusion, aberrant KIF2A signifies tumor size and invasion, and may help to predict prognosis in patients with PTC.

Expression of BCRP/ABCG2 Protein in Invasive Breast Cancer and Response to Neoadjuvant Chemotherapy

Background: Breast cancer resistance protein (BCRP), or ATP-binding cassette subfamily G member 2 (ABCG2), is an ATP-binding cassette (ABC) transporter that mediates energy-dependent transport of substrate drugs out of the cell. Its overexpression may contribute to intrinsic drug resistance in vitro. However, the current literature has not yet clarified the clinical significance of BCRP/ABCG2 in invasive breast carcinoma. Objectives: The purpose of this study was to validate the expression of BCRP/ABCG2 in invasive breast carcinoma and its role in response to neoadjuvant chemotherapy. Methods: In this study, a pretherapeutic core biopsy was performed in 222 patients. BCRP/ABCG2 expression in carcinoma tissue was measured by immunohistochemistry. BCRP/ABCG2 expression correlations with clinicopathological features, molecular subtypes, and therapy response after neoadjuvant chemotherapy were investigated. Results: The results showed that BCRP/ABCG2 was expressed in different molecular subtypes. The proportions of patients with high BCRP/ABCG2 expression were similar in luminal A and luminal B tumors (luminal B, 80%; luminal A, 78%), compared with other molecular subtypes (triple-negative, 63%; HER2+, 58%, p = 0.05). BCRP/ABCG2 expression and the number of lymphatic metastases (p = 0.001) and tumor size (p = 0.011) demonstrated a statistically significant correlation. Low BCRP/ABCG2 expression was associated with an increased pathological complete response (pCR) rate of 38%, higher than the 19% in tumors with high BCRP/ABCG2 expression (p = 0.002). In multivariable analysis, BCRP/ABCG2 and hormone receptor (HR) expression were identified as independent risk factors of pCR (p = 0.003 and p = 0.013, respectively). Conclusions: BCRP/ABCG2 is highly expressed in HR-positive breast cancer. High BCRP/ABCG2 expression is associated with lymphatic metastasis, tumor size, and poor pCR. BCRP/ABCG2 may be a novel potential biomarker that can predict clinical progression and therapy response after neoadjuvant chemotherapy.

Inhibition of MIR4435-2HG on Invasion, Migration, and EMT of Gastric Carcinoma Cells by Mediating MiR-138-5p/Sox4 Axis.

BackgroundThe previous investigations have identified that long non-coding RNA (lncRNAs) act as crucial regulators in gastric carcinoma. However, the function of lncRNA MIR4435-2HG in the modulation of gastric carcinoma remains elusive. Here, we aimed to explore the role of MIR4435-2HG in gastric carcinoma.MethodThe Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were applied to select the differently expressed lncRNAs in gastric carcinoma. The qRT-PCR was applied to analyze MIR4435-2HG expression in carcinoma tissues and cell lines. The effect of MIR4435-2HG on proliferation, invasion, migration, and apoptosis of gastric carcinoma cells was detected by Cell Counting Kit-8 (CCK-8) assays, transwell assays, and flow cytometry in vitro. A subcutaneous tumor model was constructed to examine the tumor growth of gastric carcinoma cells after knocking out MIR4435-2HG. RNA immunoprecipitation and luciferase reporting assays were applied to evaluate the interaction of MIR4435-2HG, miR-138-5p, and Sox4.ResultsThe bioinformatics analysis based on TCGA and GEO databases indicated that MIR4435-2HG was obviously elevated in gastric carcinoma samples. The qRT-PCR analysis revealed that MIR4435-2HG was upregulated in clinical gastric carcinoma tissues and cells. The high expression of MIR4435-2HG is associated with the poor survival rate of patients. The knockout of MIR4435-2HG could repress the proliferation, invasion, migration, and epithelial–mesenchymal transition (EMT) and accelerate the apoptosis of gastric carcinoma cells. Moreover, the deletion of MIR4435-2HG was able to attenuate the tumor growth in vivo. Mechanically, we identified that MIR4435-2HG enhanced Sox4 expression by directly interacting with miR-138-5p as a competitive endogenous RNA (ceRNA) in gastric carcinoma cells, in which Sox4 was targeted by miR-138-5p.ConclusionMIR4435-2HG is elevated in gastric carcinoma cells and contributes to the growth, metastasis, and EMT of gastric carcinoma cells by targeting miR-138-5p/Sox4 axis. MIR4435-2HG may be applied as a potential therapeutic target in gastric carcinoma.

Integrated Profiling Identifies CCNA2 as a Potential Biomarker of Immunotherapy in Breast Cancer.

IntroductionBreast cancer is the main reason for cancer-related deaths in women and the most common malignant cancer among women. In recent years, immunosuppressive factors have become a new type of treatment for cancer. However, there are no effective biomarkers for breast cancer immunotherapy. Therefore, exploring immune-related biomarkers is presently an important topic in breast cancer.MethodsGene expression profile data of breast cancer from The Cancer Genome Atlas (TCGA) was downloaded. Scale-free gene co-expression networks were built with weighted gene co-expression network analysis. The correlation of genes was performed with Pearson’s correlation values. The potential associations between clinical features and gene sets were studied, and the hub genes were screened out. Gene Ontology and gene set enrichment analysis were used to reveal the function of hub gene in breast cancer. The gene expression profiles of GSE15852, downloaded from the Gene Expression Omnibus database, were used for hub gene verification. In addition, candidate biomarkers expression in breast cancer was studied. Survival analysis was performed using Log rank test and Kaplan–Meier. Immunohistochemistry was used to analyze the expression of CCNA2.ResultsA total of 6 modules related to immune cell infiltration were identified via the average linkage hierarchical clustering. According to the threshold criteria (module membership >0.9 and gene significance >0.35), a significant module consisting of 13 genes associated with immune cells infiltration were identified as candidate hub genes after performed with the human protein interaction network. And 3 genes with high correlation to clinical traits were identified as hub genes, which were negatively associated with the overall survival. Among them, the expression of CCNA2 was increased in metastatic breast cancer compare with non-metastatic breast cancer, who underwent immunotherapy. Immunohistochemistry results showed that CCNA2 expression in carcinoma tissues was elevated compared with normal control.DiscussionCCNA2 identified as a potential immune therapy marker in breast cancer, which were first reported here and deserved further research.

PKM2 in Canine Mammary Tumors: Parallels to Human Breast Cancer.

PKM2 is a pyruvate kinase isoform that is the final and rate-limiting step in aerobic glycolysis in tumor cells. Increased expression of PKM2 has been detected in human cancers. The present study examined the expression of PKM2 in canine mammary tumors and assessed its prognostic significance. Paraffin sections of 5 adenomas, 67 carcinomas, and 5 samples of nonneoplastic hyperplasia from 77 dogs, aged 8 to 18 y, were evaluated. Significantly higher levels of PKM2 were detected among the carcinomas compared with all other tissues examined. The level of PKM2 expression in carcinoma tissue correlated positively with the tumor grade. These findings suggest that PKM2 may have a similar role in canine mammary tumors to its role in human breast cancer. As such, canine mammary tumors may be useful models for studies focused on the progression of human neoplastic disease.

The immunomodulatory role of tumor Syndecan-1 (CD138) on ex vivo tumor microenvironmental CD4+ T cell polarization in inflammatory and non-inflammatory breast cancer patients.

Herein, we aimed to identify the immunomodulatory role of tumor Syndecan-1 (CD138) in the polarization of CD4+ T helper (Th) subsets isolated from the tumor microenvironment of inflammatory breast cancer (IBC) and non-IBC patients. Lymphocytes and mononuclear cells isolated from the axillary tributaries of non-IBC and IBC patients during modified radical mastectomy were either stimulated with the secretome as indirect co-culture or directly co-cultured with control and Syndecan-1-silenced SUM-149 IBC cells. In addition, peripheral blood mononuclear cells (PBMCs) of normal subjects were used for the direct co-culture. Employing flow cytometry, we analyzed the expression of the intracellular IFN-γ, IL-4, IL-17, and Foxp3 markers as readout for basal and co-cultured Th1, Th2, Th17, and Treg CD4+ subsets, respectively. Our data revealed that IBC displayed a lower basal frequency of Th1 and Th2 subsets than non-IBC. Syndecan-1-silenced SUM-149 cells significantly upregulated only Treg subset polarization of normal subjects relative to controls. However, Syndecan-1 silencing significantly enhanced the polarization of Th17 and Treg subsets of non-IBC under both direct and indirect conditions and induced only Th1 subset polarization under indirect conditions compared to control. Interestingly, qPCR revealed that there was a negative correlation between Syndecan-1 and each of IL-4, IL-17, and Foxp3 mRNA expression in carcinoma tissues of IBC and that the correlation was reversed in non-IBC. Mechanistically, Syndecan-1 knockdown in SUM-149 cells promoted Th17 cell expansion via upregulation of IL-23 and the Notch ligand DLL4. Overall, this study indicates a low frequency of the circulating antitumor Th1 subset in IBC and suggests that tumor Syndecan-1 silencing enhances ex vivo polarization of CD4+ Th17 and Treg cells of non-IBC, whereby Th17 polarization is possibly mediated via upregulation of IL-23 and DLL4. These findings suggest the immunoregulatory role of tumor Syndecan-1 expression in Th cell polarization that may have therapeutic implications for breast cancer.

The p53-signaling pathway and colorectal cancer: Interactions between downstream p53 target genes and miRNAs

IntroductionWe examined expression of genes in the p53-signaling pathway. We determine if genes that have significantly different expression in carcinoma tissue compared to normal mucosa also have significantly differentially expressed miRNAs. We utilize a sample of 217 CRC cases. MethodsWe focused on fold change (FC) > 1.50 or <0.67 for genes and miRNAs, that were statistically significant after adjustment for multiple comparisons. We evaluated the linear association between the differential expression of miRNA and mRNA. miRNA:mRNA seed-region matches also were determined. ResultsEleven dysregulated genes were associated with 37 dysregulated miRNAs; all were down-stream from the TP53 gene. MiR-150-5p (HR = 0.82) and miR-196b-5p (HR 0.73) significantly reduced the likelihood of dying from CRC when miRNA expression increased in rectal tumors. ConclusionsOur data suggest that activation of p53 from cellular stress, could target downstream genes that in turn could influence cell cycle arrest, apoptosis, and angiogenesis through mRNA:miRNA interactions.

Clinicopathological significance of galectin-1 expression and percentage of galectin-1-expressing T cells in clear-cell renal cell carcinoma.

This study investigates the clinical significance of galectin-1 expression in carcinoma tissues, plasma, and lymphocytes of patients with clear-cell renal cell carcinoma (RCC). Galectin-1 expression was investigated, using immunohistochemistry, in 91 clear-cell RCC tissue sections, five angioleiolipomas tissue sections, and three oncocytomas tissue sections. As controls, normal tissue sections adjacent to each tumour and six benign renal tumour sections were examined. Plasma galectin-1 levels as measured by ELISA were compared in 39 patients. Proportions of galectin-1 expressing CD4+ and galectin-1 expressing CD8+ T lymphocytes in peripheral blood of these patients were detected by flow cytometry. The positive expression rate of galetin-1 in 91 clear-cell RCC tissues sections by immunohistochemistry was 87 (95.6%), with weak expression rate of 35.2 (32/91), moderate expression rate of 51.6% (47/91), and strong expression rate of 13.2% (12/91); whereas 25% (2/8) of renal benign tumour sections showed weak galectin-1 expression, 91.2% (83/91) of non-tumor tissues adjacent to carcinomas had negative expression of galectin-1, and another six (75%) renal benign tumour sections had negative galectin-1 expression. Plasma galectin-1 levels between patients with clear-cell RCC and with benign tumours were not significantly difference (p>0.05). In patients with clear-cell RCC, we found a significantly higher proportion of galectin-1-expressing CD4+ lymphocytes (p<0.05) and galectin-1-expressing CD8+ lymphocytes (p<0.05) than in patients with benign tumours. Moreover, the level of galectin-1 expression was positively associated with stage and Fuhrman grade of clear-cell RCC. Our results suggest that high level of galectin-1 expression in clear-cell RCC tissues may be a useful marker for clear-cell RCC. Our findings also reveal a new clinical significance of galectin-1 - that high proportions of galectin-1-expressing CD4+ and CD8+ lymphocytes were positively associated with poor clinicopathological features.

B-cell specific Moloney leukemia virus insert site 1 and peptidyl arginine deiminase IV positively regulate carcinogenesis and progression of esophageal squamous cell carcinoma.

High expression of B-cell specific Moloney leukemia virus insert site 1 (Bmi-1) and peptidyl arginine deiminase IV (PADI4) is associated with esophageal carcinoma. However, few studies have investigated the association between the Bmi-1 and PADI4 genes. The aim of the present study was to evaluate the expression of Bmi-1 and PADI4 and identify the association between the Bmi-1 and PADI4 genes in esophageal squamous cell carcinoma (ESCC) tissues. Bmi-1 and PADI4 gene expression levels were measured using immunohistochemistry, western blotting and reverse transcription-quantitative polymerase chain reaction in ESCC tissues from 86 patients who had not received pre-operative chemoradiation. The results revealed that the Bmi-1 and PADI4 genes had increased expression in carcinoma tissues compared with pericarcinous tissue (P<0.05). Bmi-1 gene expression was revealed to be associated with differentiation degree, clinical stage and lymph node metastasis (P<0.05), but had no association with gender, age or depth of invasion (P>0.05). The expression of PADI4 was associated with clinical stage, depth of invasion and lymph node metastasis (P<0.05), but was not associated with gender, age or differentiation degree (P>0.05). In addition, there was a positive association between Bmi-1 and PADI4 gene expression in ESCC (P<0.05). These results indicated that Bmi-1 and PADI4 positively regulate carcinogenesis and progression of ESCC.

Histone H3 Acetyl K9 and Histone H3 Tri Methyl K4 as Prognostic Markers for Patients with Cervical Cancer

Chromatin remodeling alters gene expression in carcinoma tissue. Although cervical cancer is the fourth most common cancer in women worldwide, a systematic study about the prognostic value of specific changes in the chromatin structure, such as histone acetylation or histone methylation, is missing. In this study, the expression of histone H3 acetyl K9, which is known to denote active regions at enhancers and promoters, and histone H3 tri methyl K4, which preferentially identifies active gene promoters, were examined as both show high metastatic potential. A panel of patients with cervical cancer was selected and the importance of the histone modifications concerning survival-time (overall survival and relapse-free survival) was analyzed in 250 cases. Histone H3 acetyl K9 staining was correlated with low grading, low FIGO (TNM classification and the International Federation of Gynecology and Obstetrics) status, negative N-status and low T-status in cervical cancer, showing a higher expression in adenocarcinoma than in squamous cell carcinoma. Cytoplasmic expression of histone H3 tri methyl K4 in a cervical cancer specimen was correlated with advanced T-status and poor prognosis. While cytoplasmic H3K4me3 expression seemed to be a marker of relapse-free survival, nuclear expression showed a correlation to poor prognosis in overall survival. Within this study, we analyzed the chemical modification of two histone proteins that are connected to active gene expression. Histone H3 acetyl K9 was found to be an independent marker of overall survival. Histone H3 tri methyl K4 was correlated with poor prognosis and it was found to be an independent marker of relapse-free survival. Therefore, we could show that chromatin remodeling plays an important role in cervical cancer biology.

High-Level Expression and Prognostic Significance of Matrix Metalloprotease-19 and Matrix Metalloprotease-20 in Human Pancreatic Ductal Adenocarcinoma.

Matrix metalloproteinase (MMP)-19 and MMP-20 are important members of the MMP family, and their roles in tumor survivorship and progression are continually reported. This work aimed to determine the expression and prognostic significance of MMP-19 and MMP-20 in pancreatic ductal adenocarcinoma (PDAC). Immunohistochemistry was used to investigate the levels of MMP-19 and MMP-20 expression in carcinoma tissues and paracancerous tissues from 102 PDAC patients. The MMP-19 and MMP-20 were, respectively, expressed in 71.6% (73/102) and 70.6% (72/102) of carcinoma tissues, and the expression was positively correlated (r = 0.643, P < 0.001). High-level expression of MMP-19 and MMP-20 was strongly correlated with aggressive clinicopathological characteristics. Kaplan-Meier analysis showed that high-level expression of MMP-19 and MMP-20 was significantly associated with decreased event-free survival (P < 0.001) and overall survival (P < 0.001). Multivariate analysis showed that high-level expression of MMP-19 could act as an independent predictive biomarker for poor event-free survival and overall survival. Levels of MMP-19 and MMP-20 expression are significantly increased in PDAC. High-level expression of MMP-19 and MMP-20 is closely correlated to progression and prognosis of PDAC, and these may be considered as promising markers for unfavorable prognoses.

Clinical significance of the expression of eukaryotic initiation factor 4 E and mammalian target of rapamycin in esophageal squamous carcinoma tissues

To explore the clinical significance of eukaryotic initiation factor 4 E (eIF4E) and mammalian target of rapamycin (mTOR) expressions in esophageal squamous carcinoma tissues. Clinicopathological data and paraffin samples of resected tumor tissue from 148 patients with esophageal squamous carcinoma undergoing resection in our department between January 2010 and December 2012 were collected retrospectively. Expressions of eIF4E and mTOR were detected in above carcinoma tissues, counterpart para-carcinoma tissues (1 cm distance to carcinoma) and normal tissues (5 cm distance to carcinoma) with Western blot and immunohistochemistry. Their relevance with clinicopathological features was analyzed. Expression of mTOR located mainly in cytoplasm and elF4E mainly in cellular membrane, presenting as yellow grains. These two markers showed strong expression in carcinoma tissues and weak or none in para-carcinoma tissues. In esophageal squamous carcinoma tissues, counterpart para-carcinoma tissues and normal tissues, mTOR protein expression was 85.8% (127/148), 35.1% (52/148) and 3.4% (5/148), eIF4E protein expression was 93.9% (139/148), 35.1% (52/148) and 12.8% (19/148), with a downtrend respectively (all P<0.05). Expressions of mTOR and eIF4E were associated with tumor invasion depth and lymphatic metastasis (all P<0.05), while mTOR expression was associated with differentiation degree (P=0.003), but eIF4E expression was not. Both expressions were not associated with gender, age, and tumor size (all P>0.05). Expressions of eIF4E and mTOR are up-regulated in esophageal squamous carcinoma tissues, which may be associated with tumor malignance and lymphatic metastasis of esophageal squamous carcinoma. Combined detection of two markers may be helpful to predict the tumor malignance and the prognosis of patients.

Abstract 4830: The correlation between CXCR7 expression and EGFR mutation in non-small cell lung cancer

Abstract Objective: To explore the correlation between CXCR7 expression and EGFR mutation in NSCLC. Materials and Methods: Forty-nine paired cases of NSCLC carcinoma and para-carcinoma tissues were analyzed for the expression of CXCR7 mRNA by RT-PCR and CXCR7 protein by IHC. EGFR mutations were detected in carcinoma tissues by ARMS. T-test, one-way ANOVA and correlation analysis were used to analyze the data with SPSS software version 18.0. Results: In NSCLC, CXCR7 protein expression in carcinoma tissues was higher than in para-carcinoma tissues (14450±2049 vs 5206±1066, p&amp;lt;0.0001), while CXCR7 mRNA was not. In NSCLC, CXCR7 mRNA and CXCR7 protein expression levels were both related to the TNM stage (p = 0.007, p = 0.008) and metastatic status (p&amp;lt;0.0001; p&amp;lt;0.0001), but not to gender, age, smoking index and pathology. EGFR and CXCR7 protein were positively correlated (r = 0.289,p = 0.044) Conclusion: Like EGFR, CXCR7 can be used as a marker to predict the prognosis and guide clinical therapy in NSCLC. Keywords: CXCR7 RDC1 EGFR NSCLC Note: This abstract was not presented at the meeting. Citation Format: Yiping Han. The correlation between CXCR7 expression and EGFR mutation in non-small cell lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4830. doi:10.1158/1538-7445.AM2015-4830

MiR-630 overexpression in hepatocellular carcinoma tissues is positively correlated with alpha-fetoprotein.

BackgroundMicroRNA-630 (miR-630) has been shown to be involved in various human malignancies. However, its role in hepatocellular carcinoma (HCC) remains unknown.Material/MethodsTaqMan qRT-PCR assay was performed to detect the expression of miR-630 in 42 pairs of HCC tissues and corresponding noncancerous hepatocellular tissues, and its correlations with clinicopathologic features and serum alpha-fetoprotein (AFP) level of patients were analyzed.ResultsThe present study found that miR-630 expression was significantly increased in HCC tissues and cells compared with their normal counterparts. miR-630 expression level did not significantly chang at stage I but was markedly increased at advanced TNM stage (stage II~III). In addition, the increased expression of miR-630 in tissues of HCC appeared in patients who exhibited elevated serum levels of AFP (>25 ng/ml), but not in those with normal AFP levels (≤25 ng/ml). The miR-630 expression in carcinoma tissues revealed a positive correlation with the levels of serum alpha-fetoprotein (AFP; R2=0.768).ConclusionsThese results suggest that miR-630 is associated with tumor progression of hepatocellular carcinoma and may be a potential prognosis indicator.

Abstract 2342: Related study on the fat mass and obesity associated FTO gene and melanoma

Abstract FTO is a Fe(II)/2-oxoglutarate-dependent oxidative DNA/RNA demethylase and plays a key role in the fat metabolism and several chronic illnesses including cancer development. Several independent SNPs in the intron 8 of the FTO gene, showed nominally significant association with risk of melanoma. But the functional regulatory mechanism of FTO protein is poorly understood. Thus, the research of downstream factors and interaction proteins of FTO may identification of the mechanism FTO participated in and discovery of the FTO pathway may provide a noval evidence to the diagnosis and put forward new targets for the treatment of melanoma. Recent reports show that there is an important link between FTO and melanoma cancer. Our recent studies find that there are differences of FTO expression between normal skin and melanoma cancer. First of all, higher FTO protein expression was detected by western blot in melanoma cancer cells, compared with primary cultured normal skin cells. However, the mRNA expression of both normal tissue and melanoma cancer are at the similar level. Secondly, FTO expression was also investigated in 80 clinical samples. Compared with normal skin tissues, malignant melanoma tissues had stronger positive immunohistochemical (IHC) staining of FTO in nucleus, and IHC scoring confirmed the significantly higher FTO protein expression in carcinoma tissues. In the normal skin tissues, FTO only expressed in basal nuclei; but in the melanoma cancer, FTO expressed in the dermal cells both at the nucleus and membrane. Especially, the expression of FTO is closely related with the pathological staging of melanoma. The increased FTO expression in melanoma carcinoma suggested that aberrant FTO expression may be an early molecular event in cancer development. Simultaneously, we focus on identifying the specific regulation function of FTO in the melanoma cancer cell, using the cDNA microarray and Two-dimensional fluorescence difference gel electrophoresis combining with MALDI-TOF-MS technique to screen the interaction proteins and their mutual regulation, determine the molecules interaction with FTO in the melanoma cancer development. Taken together, these data demonstrated that there is an important link between FTO and melanoma cancer, FTO gene plays an important role in melanoma pathogenesis. Note: This abstract was not presented at the meeting. Citation Format: Tianhui Niu, Min Xiong, Yan Tian. Related study on the fat mass and obesity associated FTO gene and melanoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2342. doi:10.1158/1538-7445.AM2014-2342

Increased miR-449a expression in colorectal carcinoma tissues is inversely correlated with serum carcinoembryonic antigen

Previously, microRNA-449a (miR-449a) has been shown to be involved in various types of cancer. However, its role in colorectal carcinoma remains unknown. The present study found that miR-449a expression was significantly increased in cultured colorectal carcinoma cells and cancer tissues obtained from 24 patients diagnosed with colorectal carcinoma, compared with the normal colorectal cells and the adjacent non-tumor tissues. The miR-449a expression in carcinoma tissues revealed an inverse correlation with the levels of serum carcinoembryonic antigen (CEA; R2=0.88). The increased expression of miR-449a appeared in the patients who exhibited normal serum levels of CEA (<5 ng/ml), but not in those with elevated CEA levels (>5 ng/ml). miR-449a expression increased at an early TNM stage (stage II) and did not change significantly at stages III and IV. These results suggested that miR-449a is involved in the development of colorectal carcinoma and may be a potential prognosis indicator.

Reduced Expression of Argininosuccinate Lyase is Closely Associated With Postresectional Survival in Hepatocellular Carcinoma

Argininosuccinate lyase (ASL) is an important enzyme in the hepatic urea cycle, and catalyzes the reversible reaction of argininosuccinate to arginine and fumarate. Its expression is significantly reduced in some hepatocellular carcinomas (HCC). In this study, we aimed to investigate the correlation of reduced ASL expression and clinicopathologic features and prognosis in HCC patients. Immunohistochemistry was used to determine the expression of ASL in HCC tissues from 61 patients who had undergone hepatic tumor resection. The correlation of ASL expression in HCC with background liver status, viral status, tumor size, portal vein invasion, histopathologic differentiation, early tumor recurrence, sex, and age were assessed with the χ(2) test. Patient survival and survival differences were determined by the Kaplan-Meier method and log-rank test. Cox regression (proportional hazard model) was used for multivariate analysis of prognostic factors. Strong positive staining was found in 39/61 HCCs and normal liver tissues, and reduced ASL staining was found in 22/61 HCCs (36.1%). Patients with low ASL expression had a significantly poorer overall survival and disease-free survival (both P<0.001). Reduced ASL expression in carcinoma tissues was also significantly associated with the tumor-node-metastasis stage and early tumor recurrence, and histopathologic differentiation and portal vein invasion (P<0.05). Cox regression analysis showed that ASL is an independent prognostic marker for HCC. Therefore, reduced ASL expression may be a novel maker for poor prognosis in HCC patients.

Increased Frequency of Foxp3+ Regulatory T Cells in Mice with Hepatocellular Carcinoma

The CD4+CD25+ regulatory T cell (Treg) is a special kind of T cell subset. Studies have showed that Treg cells are involved in a number of physiological processes and pathologic conditions such as autoimmune diseases, transplantation tolerance and cancer. Tregs with unique capacity for immune inhibition can impair anti-tumour immunity and help tumor cells to escape from immune surveillance. The aim of our study was to investigate whether Tregs are involved in hepatocellular carcinoma (HCC). A BABL/C mouse with HCC in situ model was established to evaluate the Treg existence in carcinoma tissues and the changes of Tregs in spleen using flow cytometry and immunohistochemistry methods. Granzyme B expression in carcinoma tissues was analyzed by immunohistochemistry to investigate the tumor local immune status. The proportion of CD4+CD25+/CD4+ spleen lymphocytes of tumor bearing mice (18.8% ± 1.26%) was found to be significantly higher than that in normal mice (9.99% ± 1.90%) (P<0.01 ). Immunohistochemistry of spleen tissue also confirmed that there was an increase in Treg in tumor-bearing mice, while in carcinomas it showed Treg cells to be present in tumor infiltrating lymphocyte areas while Granzyme B was rarely observed. Anti-tumour immunity was suppressed, and this might be associated with the increase of Tregs. Our observations suggest that the CD4+CD25+Treg/ CD4+ proportion in spleen lymphocytes can be a sensitive index to evaluate the change of Tregs in hepatocellular carcinoma mice and the Treg may be a promising therapeutic target for cancer.