High expression of MMP19 is associated with poor prognosis in patients with colorectal cancer.

BACKGROUND: Matrix metalloproteinase 19 (MMP19) is a member of zinc-dependent endopeptidases, which have been involved in various physiological and pathological processes. Its expression has been demonstrated in some types of cancers, but the clinical significance of MMP19 in colorectal cancer (CRC) has not been reported. Thus, we aimed to analyze the clinical significance of MMP19 in CRC in present study. METHODS: The expression of MMP19 was first explored in The Cancer Genome Atlas (TCGA) cohort, and then validated in the GSE39582 cohort and our own database. Clinicopathological features and survival rate were also investigated. RESULTS: MMP19 was found to be a predictor for overall survival (OS) in both univariate (hazard ratio [HR]: 1.449, 95% confidence interval [CI]: 1.108-1.893, P = 0.007) and multivariate survival analyses (HR: 1.401, 95% CI: 1.036-1.894, P = 0.028) in the TCGA database. MMP19 was further validated as an independent factor for recurrence free survival in the GSE39582 database by both univariate analysis (HR: 2.061, 95%CI: 1.454-2.921, P < 0.001) and multivariate analysis (HR = 1.470, 95% CI: 1.025-2.215, P = 0.032). In an in-house cohort, MMP19 was significantly upregulated in CRC tissues when compared with their adjacent normal controls (P < 0.001). Ectopic MMP19 expression was positively associated with lymph node metastases (P = 0.029), intramural vascular invasion (P = 0.015) and serum carcinoembryonic antigen levels (P = 0.045). High MMP19 expression correlated with a shorter OS (HR = 5.595; 95% CI: 2.573-12.164; P < 0.001) and disease free survival (HR = 4.699; 95% CI: 2.461-8.974; P < 0.001) in multivariate cox regression analysis. CONCLUSIONS: Expression of MMP19 was upregulated in CRC. High expression of MMP19 was determined to be an independent and poor prognostic factor in CRC. These results suggest that MMP19 may be a good biomarker for CRC.

Screening key lncRNAs for human rectal adenocarcinoma based on lncRNA-mRNA functional synergistic network.

BACKGROUND: Rectal adenocarcinoma (READ) is one of the deadliest malignancies, and the molecular mechanisms underlying the initiation and development of READ remain largely unknown. In this study, we aimed to find key long noncoding RNAs (lncRNAs) and mRNAs in READ by RNA sequencing. METHODS: RNA sequencing was performed to identify differentially expressed mRNAs (DEmRNAs) and lncRNAs (DElncRNAs) between READ and normal tissue. READ-specific protein-protein interaction (PPI), DElncRNA-DEmRNA coexpression, and DElncRNA-nearby DEmRNA interaction networks were constructed. DEmRNAs and DEmRNAs coexpressed with DElncRNAs were functionally annotated. RESULTS: A total of 2113 DEmRNAs and 150 DElncRNAs between READ and normal tissue were identified. The PPI network identified several hub proteins, including CDK1, AURKB, CDC6, FOXQ1, NUF2, and TOP2A. The DElncRNA-DEmRNA coexpression and DElncRNA-nearby DEmRNA interaction networks identified some hub lncRNAs, including CCAT1, LOC105374879, GAS5, and B3GALT5-AS1. The colorectal cancer pathway, the intestinal immune network for IgA production and the p53 signaling pathway were three pathways significantly enriched in DEmRNAs and DEmRNAs coexpressed with DElncRNAs. MSH6 coexpressed with two DElncRNAs (LOC105374879 and CASC15) and BCL2 coexpressed with B3GALT5-AS1 were significantly enriched in the colorectal cancer signaling pathway. TNFRSF17 coexpressed with B3GALT5-AS1 was enriched in the intestinal immune network for IgA production. CCNB2 coexpressed with LOC105374879 was enriched in the p53 signaling pathway. CONCLUSION: A total of four DEmRNAs (MSH6, BCL2, TNFRSF17, and CCNB2) and three DElncRNAs (LOC105374879, CASC15, and B3GALT5-AS1) may be involved in the pathogenesis of READ; this data may contribute to understanding the mechanisms of READ and the development of therapeutic strategies for READ.

The KLF14 Transcription Factor Regulates Glycolysis by Downregulating LDHB in Colorectal Cancer.

The Krüppel-like transcription factor 14 (KLF14) is a critical regulator of a wide array of biological processes. However, the role of KLF14 in colorectal cancer (CRC) isn't fully investigated. This study aimed to explore the clinicopathological significance and potential role of KLF14 in the carcinogenesis and progression of CRC. A tissue microarray consisting of 185 samples from stage I-III CRC patients was adopted to analyze the correlation between KLF14 expression and clinicopathological parameters, as well as overall survival (OS) and disease-free survival (DFS). The underlying mechanisms of altered KLF14 expression on glycolysis were studied using in vitro and patients' samples. The results showed that KLF14 expression was downregulated in CRC than their normal controls. Low KLF14 expression correlated with advanced T stage (P< 0.001) and N stage (P= 0.040), and larger tumor size (P= 0.008). Lost KLF14 expression implied shorter OS and DFS after colectomy in both univariate and multivariate survival analysis (P<0.05). Experimentally, restore KLF14 expression significantly decreased the rate of glycolysis both in vitro and in patients' sample. Mechanically, KLF14 regulated glycolysis by downregulating glycolytic enzyme LDHB. Collectively, KLF14 is a novel prognostic biomarker for survival in CRC, and downregulation of KLF14 in CRC prompts glycolysis by target LDHB. Hence, KLF14 could constitute potential prognostic predictors and therapeutic targets for CRC.

NOTCH4 Is a Novel Prognostic Marker that Correlates with Colorectal Cancer Progression and Prognosis.

Notch family plays vital role in carcinogenesis and progression of various cancer, however, its clinical significance and prognostic value in colorectal cancer isn't fully investigated. In present study, we first investigated the NOTCH4 expression in The Cancer Genome Atlas (TCGA) (n=361) and GSE39582 (n=474) database and then validated with our own database (n=248). The transcriptional and protein levels of NOTCH4 were evaluated by RT-PCR and immunohistochemistry study, respectively. Univariate and multivariate survival analyses were performed to explore the relationship between various prognostic factors and survival outcomes. In the univariate analysis, NOTCH3 and NOTCH4 were significantly correlated with prognosis in TCGA and GSE39582 database, respectively (P<0.05). For NOTCH3 has been studied in CRC, we chosen NOTCH4 for further study. NOTCH4 mRNA was higher in liver metastases than their primary colorectal cancer or normal mucosa. Increased NOTCH4 levels significantly correlated with advanced N stage (P= 0.002), M stage (P= 0.002), lymphovascular invasion (P= 0.026), and CEA status (P= 0.030). Patients with high NOTCH4 expression had shorter 5-year disease-free survival (DFS) (HR 6.809; 95% CI 3.334-13.904; P< 0.001) and overall survival (OS) (HR 6.476; 95% CI 3.307-12.689; P<0.001) than those with low NOTCH4 expression. Multivariate survival analysis demonstrated that NOTCH4 was an independent prognostic biomarker for both DFS (HR 7.848; 95% CI 3.777-16.308; P<0.001) and OS (HR 5.323; 95% CI 2.668-10.623; P<0.001).Collectively, NOTCH4 may play critical role in colorectal cancer progression and could serve as a novel biomarker to predict survival after colectomy.