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Objective: Polo‐like kinase 1 (PLK1), a serine/threonine‐protein kinase, functions as a potent oncogene in the initiation and progression of tumor. The aim of this study is to assess potential correlations between PLK1 expression and immune infiltration in breast cancer (BRCA) and construct a PLK1‐based immune risk model applicable for prognosis and treatment response prediction in BRCA. Methods: We collected data on PLK1 gene expression in BRCA patients from The Cancer Genome Atlas (TCGA) database. Thereafter, we analyzed the associations of PLK1 expression with immune cell infiltration and immunomodulators, and established a prognostic risk model based on seven PLK1‐associated immunomodulator genes and a nomogram for survival prediction. Results: BRCA prognosis, clinical stage progression, and tumor classification were all shown to be substantially correlated with PLK1 expression. The PLK1 gene was significantly enriched in T cell and B cell receptors and molecules of the chemokine signaling pathways. Specifically, PLK1 expression was positively correlated with the CD8+ T cell and regulatory T cell (Tregs) activation and negatively correlated with M2 macrophage infiltration. The seven‐genes‐based risk model could serve as an independent prognostic factor of BRCA. The risk model was markedly correlated with the expression of programmed cell death protein 1/programmed cell death ligand 1 (PD‐1/PD‐L1; both p < 0.001) immune checkpoints, and tumor mutation burden (TMB). High‐ and low‐risk BRCA patients identified by the risk model responded differently to anti‐PD‐1 and/or anti‐CTLA4 therapy, as well as common chemotherapy drugs, like cisplatin, paclitaxel, and gemcitabine. Conclusion: This PLK1‐based immune risk model can effectively predict the prognosis and tumor progression of BRCA, identify gene mutations, and evaluate patient's response toward immunotherapy and chemotherapy regimens. [ABSTRACT FROM AUTHOR]

Background: Collagen (COL) genes, play a key role in tumor invasion and metastasis, are involved in tumor extracellular matrix (ECM)-receptor interactions and focal adhesion pathways. However, studies focusing on the diagnostic value of the COL4 family in stomach adenocarcinoma (STAD) are currently lacking. Methods: The TCGA database was employed to retrieve the clinical features and RNA sequencing expression profiles of patients with STAD. We conducted an investigation to examine the expression disparities between STAD and adjacent normal tissues. Kaplan-Meier survival analysis was utilized to assess their prognostic significance, while Spearman correlation analysis was employed to determine their association with immune checkpoint genes and immunomodulatory molecules. Furthermore, GO and KEGG analyses were performed on the COL4s-related genes, revealing potential biological pathways through gene set enrichment analysis (GSEA). Subsequently, we explored the extent of immune infiltration of the COL4 family in STAD using the TIMER database. Lastly, the expression levels of the COL4 family in STAD were further validated through quantitative PCR (qPCR) and western blot techniques. Results: The expression levels of COL4A1/2 were significantly upregulated, while COL4A5/6 were conspicuously downregulated in STAD. The survival analysis revealed that the upregulated COL4s indicated poorer overall survival, first progression and post-progression survival outcomes. Additionally, our findings demonstrated a positive correlation between the expressions of COL4A1/2/3/4 and the infiltration of immune cells, including CD8 + T cells, dendritic cells, macrophages, neutrophils and CD4 + T cells. Further correlation analysis uncovered a favorable association between the expression of COL4A1/2/3/4 and various crucial immunomodulatory molecules, immunological checkpoint molecules, and chemokines. Quantitative PCR analysis confirmed that the expression patterns of COL4A1/3/4/6 genes aligned with the finding from the TCGA database. However, gastric cancer cells exhibited downregulation of COL4A2. Consistently, the protein level of COL4A1 was elevated, whereas the protein level of COL4A2 was reduced in the gastric cancer cell lines. Conclusion: COL4s could potentially serve as biomarkers for diagnosing and predicting the prognosis of STAD. [ABSTRACT FROM AUTHOR]

Abstract: In adults with precursor-B lymphoblastic leukemia (BCP-ALL) there remain a majority of patients who fall in an intermediate cytogenetics risk category with a heterogenous outcome. We analyzed immunophenotypic and cytogenetic factors retrospectively in 126 consecutive adults with BCR-ABL negative BCP-ALL who were treated with a pediatric-based protocol at a single institution over a 10 year period. In addition to age, WBC and cytogenetic findings, CD13 positivity was an independent poor prognostic indicator for overall survival (OS, p =0.049), event-free survival (EFS, p =0.013), and relapse-free survival (RFS, p <0.001). The prognostic value of CD13 was primarily seen in patients with normal or intermediate risk cytogenetics. A risk model that includes age>60 years, WBC>30×109/L, SWOG high/very high risk cytogenetics and CD13 positivity, performs better than a risk model of cytogenetics alone for stratifying patients by OS (p =0.001), EFS (p =7×10−4) and RFS (p =8×10−4). Incorporating CD13 into a scoring system provides high discrimination for relapse risk and survival. [Copyright &y& Elsevier]

Background: Laminin subunit gamma-1 (LAMC1) is a major extracellular matrix molecule involved in the tumor microenvironment. Knowledge of the biological features and clinical relevance of LAMC1 in cancers remains limited. Methods: We conducted comprehensive bioinformatics analysis of LAMC1 gene expression and clinical relevance in pan-cancer datasets of public databases and validated LAMC1 expression in glioma tissues and cell lines. The association and regulatory mechanism between hypoxia inducible factor-1α (HIF-1α) and LAMC1 expression were explored. Results: LAMC1 expression in most cancers in The Cancer Genome Atlas (TCGA) including glioma was significantly higher than that in normal tissues, which had a poor prognosis and were related to various clinicopathological features. Data from the Chinese Glioma Genome Atlas also showed high expression of LAMC1 in glioma associated with poor prognoses. In clinical glioma tissues, LAMC1 protein was highly expressed and correlated to poor overall survival. LAMC1 knockdown in Hs683 glioma cells attenuated cell proliferation, migration, and invasion, while overexpression of LAMC1 in U251 cells leads to the opposite trend. Most TCGA solid cancers including glioma showed enhancement of HIF-1α expression. High HIF-1α expression leads to adverse prognosis in gliomas, besides, HIF-1α expression was positively related to LAMC1. Mechanistically, HIF-1α directly upregulated LAMC1 promotor activity. Hypoxia (2% O2)-treated Hs683 and U251 cells exhibited upregulated HIF-1α and LAMC1 expression, which was significantly attenuated by HIF-1α inhibitor YC-1 and accompanied by attenuated cell proliferation and invasion. Conclusions: High expression of LAMC1 in some solid tumors including gliomas suggests a poor prognosis. The hypoxic microenvironment in gliomas activates the HIF-1α/LAMC1 signaling, thereby promoting tumor progression. Targeted intervention on the HIF-1α/LAMC1 signaling attenuates cell growth and invasion, suggesting a new strategy for glioma treatment. [ABSTRACT FROM AUTHOR]

Gene therapy with adenoviral vectors is a promising new approach for the treatment of refractory advanced breast cancer. Strategies to restrict adenoviral-mediated therapeutic gene expression are important to avoid harming normal cells. Fatty acid synthase (FAS) is overexpressed in several human cancers. FAS is highly expressed in infiltrating breast cancer tissue, and always associated with malignant phenotypes and poor prognosis. In this study, expression of the FAS was evaluated in three breast cancer cell lines. A 680 bp-FAS promoter was cloned and its transcriptional activity was analyzed in breast cancer cell lines. We made a recombinant adenovirus construct carrying herpes simplex virus thymidine kinase (HSV-TK) driven by human FAS promoter (Ad-FAS-TK) and analyzed its target cytotoxicity in vitro and in vivo against human breast cancer cells combined with prodrug ganciclovir (GCV). The results show that the expression of FAS varies in the three breast cancer cell lines examined (respectively, SK-Br3>MCF-7>MDA-MB-231), but FAS promoter can initiate relative high transcriptional activities in all three kinds of cancer cells while little in normal fibroblast cells. Furthermore, FAS promoter can drive the therapeutic gene in a wider range of human breast cancers than cerbB2 promoter and exhibit a stronger activity than midkine (MK) promoter. Combination of Ad-FAS-TK and GCV treatment exhibited strong-targeted cytotoxic effect on breast cancer cells but showed little activity in normal fibroblast cells. The tumorigenic capability of breast cancer cells treated with Ad-FAS-TK/GCV was completely inhibited in vitro and in vivo assays. In conclusion, adenoviral-mediated suicide gene therapy controlled by tumor associated-FAS promoter can induce specific cytotoxic effect on human breast cancer cells in vitro and in vivo. So it is a promising target for the development of gene therapy against breast cancers. [ABSTRACT FROM AUTHOR]

BACKGROUND: Hepatocellular carcinoma (HCC) has a high degree of malignancy and poor prognosis. N6-methyladenosine (m6A) modifications and microRNAs (miRNAs) play pivotal roles in tumorigenesis and development. However, the role of m6A-related miRNAs in HCC has not been clarified yet. This study aimed to identify the role of m6A-miRNAs in HCC prognosis through bioinformatics analysis. METHODS: The clinicopathological information and RNA sequencing data of 369 HCC tumor tissues and 49 tumor-adjacent tissues were downloaded from the TCGA database. A total of 23 m6A regulators were extracted to evaluated the m6A-related miRNAs using Pearson's correlation analysis. Then, we selected prognosis-related m6A-miRNAs using a univariate Cox regression model and used the consensus cluster analysis to explore the characteristics of the m6A-miRNAs. The coefficient of the least absolute shrinkage and selection operator (LASSO) Cox regression was applied to construct a prognostic risk score model. The receiver operated characteristic (ROC) analysis was applied to evaluate the prognostic value of the signature. The biological functions of targeted genes were predicted by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Then, to validate the potential predictive value for prognosis, the miRNA expression profiles from the GSE76903 and GSE6857 were used. Single sample Gene Set Enrichment Analysis (ssGSEA) and Estimation of Stromal and Immune cells in Malignant Tumor tissues using Expression data (ESTIMATE) were applied to assess the immune microenvironment of HCC. Additionally, a meta-analysis was used to verify the prognostic value of the m6A-microRNAs. RT-PCR was applied to validated the expression of miRNAs in HCC tissues. Cell viability, transwell assay and RNA m6A dot blot assays of HCC cells was applied to access the function of miR-17-5p. RESULTS: The expression of 48 m6A-related miRNAs was identified and 17 prognostic m6A-miRNAs was discovered. The expression profile of those 17 miRNAs was divided into three clusters, and these clusters were associated with the tumor microenvironment (TME) and prognosis. The nine m6A-related miRNA signature was associated with the prognosis of HCC, the AUC of the ROC was 0.771(TCGA dataset), 0.788(GSE76903) and 0.646(GSE6857). The TME and the expression of immune checkpoint molecules were associated with the risk score. The meta-analysis also validated the prognostic value of the m6A-related miRNAs (miR182-5p (HR:1.58, 95%CI:1.04-2.40) and miR-17-5p (HR:1.58, 95%CI: 1.04–2.40)). The expression of miR-17-5p was upregulated in HCC tissues and miR-17-5p showed an oncogenic role in HCC cells. CONCLUSION: The clinical innovation is the use of m6A-miRNAs as biomarkers for predicting prognosis regarding immunotherapy response in HCC patients. [ABSTRACT FROM AUTHOR]

ADP-ribosylation factor-like protein (ARL) family members (ARLs) may regulate the malignant phenotypes of cancer cells. However, relevant studies on ARLs in breast cancer (BC) are limited. In this research, the expression profiles, genetic variations, and prognostic values of ARLs in BC have been systematically analyzed for the first time using various databases. We find that ARLs are significantly dysregulated in BC according to the TCGA database, which may result from DNA methylation and copy number alteration. Prognostic analysis suggests that ARL11 is the most significant prognostic indicator for BC, and higher ARL11 predicts worse clinical outcomes for BC patients. Further functional enrichment analysis demonstrates that ARL11 enhances the immunosuppression in BC, and dysregulation of ARL11 is significantly associated with immune infiltration in various types of cancer. Our results demonstrate the potential of ARL11 as an immune therapeutic target for BC. [ABSTRACT FROM AUTHOR]

Background: While the epidemiologic association between hepatitis B virus (HBV) infection and diffuse large B-cell lymphoma (DLBCL) is established, little is known about the pathological characteristics and outcome of DLBCL arising in patients with HBV infection. Methods: We retrospectively studied a cohort of 420 patients with DLBCL for the incidence of HBV infection, and the clinicopathologic features and prognostic factors in HBsAg-positive DLBCL patients in China, a hepatitis B endemic area. Results: In our study, 127 (30.2%) patients were HBsAg-positive. HBsAg-positive DLBCL displayed a younger median onset age (50 vs. 54 years, P = 0.002), more frequent involvement of the spleen (19.7% vs. 6.1%, P < 0.001), less frequent involvement of the small and large intestine (2.3% vs. 11.2%, P = 0.003), more advanced disease (stage III/IV: 56.7% vs. 45.1%, P = 0.028), and lower expression rate of MYC (49.1% vs. 66.7%, P = 0.026). The median follow-up time was 61.9 months. Univariate analysis showed that there was no significant difference in overall survival (OS) between HBsAg-negative and -positive DLBCL (P = 0.577). In the HBsAg-positive DLBCL subgroup, age older than 60 years, advanced disease, elevated lactate dehydrogenase (LDH), spleen involvement, B symptoms (fever, night sweats, weight loss), and double expressers of MYC and BCL2 had a significantly worse outcome, and patients treated with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) had a better prognosis. Multivariate analysis further confirmed that spleen involvement and rituximab use were independent prognostic factors in HBsAg-positive DLBCL patients. Conclusions: Our study indicates that HBsAg-positive DLBCL has unique clinicopathological features and independent prognostic factors. Moreover, under antiviral prophylaxis, the survival of DLBCL patients with HBV infections was comparable to that of HBV-negative patients, and the use of rituximab significantly improved OS in HBsAg-positive DLBCL patients. [ABSTRACT FROM AUTHOR]

The response to radiation therapy (RT) is closely associated with DNA damage repair. X-ray repair cross-complementing group-1 (XRCC1) is a key gene in the DNA damage repair pathway, and SNPs in this gene alter the expression and activity of its effector protein, which may in turn affect sensitivity to RT. Therefore, the course of tumor treatment and local control rate can be influenced. In the present study, a group of 158 patients with nasopharyngeal carcinoma (NPC) who received intensity-modulated RT at Fujian Cancer Hospital (Fuzhou, China) between July 2012 and October 2013 were included in retrospective chart review and followed up. Plasma was collected before treatment for genotype analysis of the three SNPs of XRCC1, namely Arg194Trp, Arg280His and Arg399Gln. Acute radiation-induced injuries sustained during treatment was graded according to the Radiation Therapy Oncology Group scoring criteria. Post-treatment follow-up was performed until August 2020. In the 158 cases of NPC, no statistically significant association was observed between the three SNPs of the XRCC1 gene and the severity of acute radiation-induced injury or prognosis. However, the AA genotype of XRCC1-Arg399Gln tended to be associated with worse progression-free survival (PFS) compared with the GA + GG genotype, although this was not significant (P=0.069). In addition, multivariate logistic analysis showed that nodal stage was significantly associated with the occurrence of acute severe radiation-induced oral mucositis (P=0.018), and there was also a trend towards an association between nodal stage and the incidence of acute severe radiation-induced pharyngitis; however, this was not statistically significant (P=0.061). Furthermore, multivariate Cox regression analysis showed that older age, distant metastasis and higher clinical stage were independent risk factors for PFS in patients with NPC. In conclusion, relying solely on the aforementioned SNPs of the XRCC1 gene may not provide a robust enough basis to predict the response to RT or prognosis in patients with NPC. [ABSTRACT FROM AUTHOR]

Purpose: Although MAGEC2 was first cloned from a human hepatocellular carcinoma (HCC) cDNA library by serum screening, the detailed attributes of MAGEC2 in HCC have rarely been elucidated. Patients and methods: In this study, The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases were consulted to analyse the expression of MAGEC2 mRNA in liver cancer. Immunohistochemistry (IHC) analysis was performed to detect MAGEC2 expression in HCC, and the relationship between MAGEC2 expression and the clinicopathological characteristics of HCC patients was evaluated. Then, we employed the short hairpin (sh)RNA-mediated knockdown of MAGEC2 in HCC cell lines to explore the function of MAGEC2 in HCC development. Finally, the expression of epithelial-mesenchymal transition (EMT) markers in HCC xenografts and clinical samples was investigated. Results: The results showed a remarkably higher level of MAGEC2 expression in HCC tissues than in noncancerous tissues, and MAGEC2 expression could be used as an independent prognostic factor for overall survival in HCC. Moreover, sh-MAGEC2 inhibited a series of HCC malignant behaviours both in vitro and in vivo. Finally, decreased MAGEC2 expression and low levels of EMT markers were detected in sh-MAGEC2 xenografts, while increased MAGEC2 expression and high levels of EMT markers were observed in invasive and metastatic HCC samples. Conclusion: Taken together, our data imply that MAGEC2 is a novel prognostic marker for HCC and that MAGEC2 significantly promotes HCC tumourigenesis by inducing EMT. Targeting MAGEC2 may provide a promising therapeutic strategy for HCC treatment. [ABSTRACT FROM AUTHOR]

Background CDK4 is a protein kinase in the CDK family important for G1/S phase cell cycle progression. However, the roles and molecular mechanisms of CDK4 triggering nasopharynx carcinogenesis are still unclear. Methods Lentiviral-vector mediated shRNA was used to suppress CDK4 expression and examine its molecular mechanisms. Using immunohistochemistry, we analyzed CDK4 protein expression in clinicopathologically characterized nasopharyngeal carcinoma (NPC) cases and nasopharyngeal tissues (NPs). Survival curves were plotted by the Kaplan-Meier method and compared using the log-rank test. Results In this investigation, we knocked down CDK4 expression and observed that NPC cell growth and cell cycle progression were significantly blocked by suppressing expression of CCND1, CDK6, and E2F1 as well as elevated p21 expression. Further, we found that reduced CDK4 expression elevated the expression of let-7c, a tumor-suppressive miRNA modulated by E2F1. We found that let-7c was markedly downregulated in NPC tissues compared to NPs and suppressed cell growth and cell cycle progression by modulating p15/p16/CDK4/E2F1 pathway. Finally, CDK4 protein was observed to be overexpressed in NPC tissues and could be considered an unfavorable prognosis factor for NPC patients although its independent prognostic value did not reach statistical significance (p = 0.087). Conclusions Our results demonstrated that overexpressed CDK4 is an unfavorable prognostic factor which suppresses the expression of tumor suppressive-factor let-7c through p21/CCND1/CDK6/E2F1 signaling, and inhibits cell proliferation by p15/p16/CDK4/E2F1 feedback signaling in NPC. [ABSTRACT FROM AUTHOR]

Expression of monocyte chemoattractant protein-1 (MCP-1) and CC chemokine receptor 2 (CCR2) and its significance has been demonstrated in some cancer cells in recent clinical studies. However, the role of tumor MCP-1 and CCR2 expression in non-small cell lung cancer (NSCLC) remains unknown. The aim of the present study was to investigate the prognostic significance of MCP-1 and CCR2 expression in NSCLC cells. The relationship between MCP-1 and CCR2 expression in NSCLC cancer cells was examined by immunohistochemical staining of surgical specimens from 134 patients. Sixty-five of these patients had follow-up records. Kaplan-Meier analysis and Cox regression model were used to assess overall survival according to the presence or absence of MCP-1 and CCR2 expression in tumor cells. MCP-1 was detected in cancer cells of 107 NSCLC (79.9 %) and CCR2 was detected in cancer cells of 39 NSCLC (29.1 %). MCP-1 expression was correlated with sex, smoking habits, histology, and tumor size. Presence of MCP-1 in tumor cells was associated with better overall survival ( P = 0.018). By multivariate analysis, MCP-1 expression in cancer cells showed an independent prognostic factor for overall survival ( P = 0.002, hazard ratio [HR] = 0.256, 95 % confidence interval [CI] = 0.106-0.616). There was no significant relationship between CCR2 expression in tumor cells and clinical and pathological characteristics. Also, no significant positive correlation between MCP-1 and CCR2 expression was revealed by Spearman correlation analysis. Our data indicate that MCP-1 is overexpressed in NSCLC cells. Its expression in cancer cells is associated with better survival in NSCLC patients. [ABSTRACT FROM AUTHOR]