MiR-124 down-regulation is critical for cancer associated fibroblasts-enhanced tumor growth of oral carcinoma.

Cancer associated fibroblasts (CAFs) are known to be involved in initiation, progression and metastasis of various cancers. However, the molecular mechanism of how CAFs affects the biological function of oral cancer (OC) has not been fully-addressed. In this study, we demonstrated that miR-124 was downregulated in oral CAFs and oral cancer cells (OCCs) when compared with matched normal fibroblasts (NFs). Hypermethylation in the promoter region of miR-124 genes was accounted for its downregulation. Interestingly, CAFs but not NFs exerted promotion effect on OCCs cell proliferation, migration and tumor growth in CAFs/NFs-OCCs co-culture. Furthermore, we identified Chemokine (C-C motif) ligand 2 (CCL2) and Interleukin 8 (IL-8) as two direct targets of miR-124. Over-expression of miR-124 in CAFs-OCCs co-culture abrogated CAFs-promoted OCCs cell growth and migration, and this inhibitory effect can be rescued by addition of CCL2 and IL-8. Finally, we showed that restoration of miR-124 expression by lentiviral infection or formulated miR-124 injection inhibited oral tumor growth in vivo suggesting miR-124 rescue could be a potential rationale for therapeutic applications in oral cancer in the future.

A CCL2/ROS autoregulation loop is critical for cancer-associated fibroblasts-enhanced tumor growth of oral squamous cell carcinoma.

Cancer-associated fibroblasts (CAFs) have been described to play critical roles in initiation, progression and metastasis of various cancers. However, the involvement of CAFs in oral cancer (OC) has not been well addressed. In this study, we demonstrate that CAFs, when cocultured with OC cells (OCCs), produce high levels of chemokine (C-C motif) ligand 2 (CCL2) and, subsequently, enhance endogenous reactive oxygen species production in cells. Oxidative stress stimulates expression of cell cycle progression proteins in OCCs, leading to promotion of OCC proliferation, migration, invasion and, OC tumor growth. On the other hand, oxidative stress triggered the activation of nuclear factor-kappaB (NF-κB) and STAT3 in CAFs, resulting in accelerating CCL2 expression. In this way, CAFs-OCCs coculture creates a favorable cytokine-rich microenvironment, beneficial for both CAFs and OCCs. In addition, upregulation of CCL2 expression has been observed in oral squamous cell carcinoma tumors and patient plasma. We also showed that inhibition of CCL2 reduced OC tumor burden in mice. Therefore, our data suggested that CCL2 represents a potential therapeutic target for treatment of OC.

Prognostic Value of Postoperative Circulating Tumor DNA in Patients With Early- and Intermediate-Stage Hepatocellular Carcinoma.

Majority of patients with resected early- and intermediate-stage liver cancer will experience postoperative recurrence. This study aimed to investigate the application of ctDNA sequencing in the postoperative period of hepatocellular carcinoma. A total of 96 patients with liver cancer were enrolled in this study. Postoperative peripheral blood samples were collected from all patients after surgery and analyzed using hybridization capture-based next-generation sequencing. Identification of at least one somatic mutation in the peripheral blood was defined as ctDNA+. Five genetic features in tumor tissues were associated with disease-free survival (DFS) using Lasso-Cox model. The area under the receiver operating characteristic curve was 0.813 and 0.882 in training and validation cohorts, respectively. The recurrence rate in ctDNA+ and ctDNA- groups was 60.9% and 27.8%, respectively. Multivariate Cox regression analysis showed that the postoperative ctDNA was an independent prognostic predictor of DFS (HR [hazard ratio]: 6.074, 95% Cl [confidence interval]: 2.648-13.929, P<0.001) and overall survival (OS) (HR: 4.829, 95% CI: 1.508-15.466, P=0.008). Combined ctDNA with AFP improved prediction performance. The median DFS was 2.0, and 8.0 months in ctDNA+/AFP-H and ctDNA+/AFP-L groups, respectively; while ctDNA-/AFP-H and ctDNA-/AFP-L groups had not reached the median time statistically (Log-rank test, P < 0.0001). Furthermore, ctDNA- patients had better prognosis than ctDNA+ patients irrespective of tumor stage. Postoperative ctDNA sequencing has great prognostic value in patients with liver cancer. Patients with positive ctDNA should receive more intensive disease monitoring and more aggressive treatment strategies to improve the survival time.

Identification of the HMMR Gene as a Diagnostic and Prognostic Biomarker in Hepatocellular Carcinoma Based on Integrated Bioinformatics Analysis.

BACKGROUND: We aimed to investigate the expression of the hyaluronan-mediated motility receptor (HMMR) gene in hepatocellular carcinoma (HCC) and nonneoplastic tissues and to investigate the diagnostic and prognostic value of HMMR. METHOD: With the reuse of the publicly available The Cancer Genome Atlas (TCGA) data, 374 HCC patients and 50 nonneoplastic tissues were used to investigate the diagnostic and prognostic values of HMMR genes by receiver operating characteristic (ROC) curve analysis and survival analysis. All patients were divided into low- and high-expression groups based on the median value of HMMR expression level. Univariate and multivariate Cox regression analysis were used to identify prognostic factors. Gene set enrichment analysis (GSEA) was performed to explore the potential mechanism of the HMMR genes involved in HCC. The diagnostic and prognostic values were further validated in an external cohort from the International Cancer Genome Consortium (ICGC). RESULTS: HMMR mRNA expression was significantly elevated in HCC tissues compared with that in normal tissues from both TCGA and the ICGC cohorts (all P values <0.001). Increased HMMR expression was significantly associated with histologic grade, pathological stage, and survival status (all P values <0.05). The area under the ROC curve for HMMR expression in HCC and normal tissues was 0.969 (95% CI: 0.948-0.983) in the TCGA cohort and 0.956 (95% CI: 0.932-0.973) in the ICGC cohort. Patients with high HMMR expression had a poor prognosis than patients with low expression group in both cohorts (all P < 0.001). Univariate and multivariate analysis also showed that HMMR is an independent predictor factor associated with overall survival in both cohorts (all P values <0.001). GSEA showed that genes upregulated in the high-HMMR HCC subgroup were mainly significantly enriched in the cell cycle pathway, pathways in cancer, and P53 signaling pathway. CONCLUSION: HMMR is expressed at high levels in HCC. HMMR overexpression may be an unfavorable prognostic factor for HCC.

Low molecular weight heparin in the treatment of severe acute pancreatitis: a multiple centre prospective clinical study.

OBJECTIVE: To study the effect of low molecular weight heparin (LMWH) in the treatment of severe acute pancreatitis (SAP). METHODS: A total of 265 SAP patients were randomly divided into two groups: firstly, the conventional treatment group (C group, n = 130; and secondly the conventional treatment plus the LMWH treatment group (LT group, n = 135). The clinical parameters, laboratory parameters and computed tomography (CT) score of pancreatic necrosis (CTSPN) in the two groups were compared. RESULTS: On admission, all the clinical parameters, laboratory parameters and CTSPN in the two groups were not significantly different (p > 0.05). However, after treatment, in LT group, the clinical presentation improvement rate and laboratory parameters improvement were significantly higher than those in C group (p < 0.05-0.01), and the acute physiology and chronic health evaluation (APACHE) II score, complication rate, mortality and mean hospital stay in LT group were obviously lower than those in C group (p < 0.05-0.01). The CT score in LT group was much lower than that in C group (p < 0.05). Two weeks after treatment FBI decreased obviously in C group, but not in LT group, and no haemorrhagic complications occurred. CONCLUSIONS: LMWH can enhance the effect of conventional treatment for SAP, and can markedly decrease the mortality of SAP. LMWH is a simple, safe, economic and effective method for treatment of SAP. It is can be used in every hospital.

Effect of lower-molecular weight heparin in the prevention of pancreatic encephalopathy in the patient with severe acute pancreatitis.

OBJECTIVE: To study the effect of lower-molecular weight heparin in the prevention of pancreatic encephalopathy (PE) in the patient with severe acute pancreatitis (SAP). METHODS: Two hundred sixty-five SAP patients were randomly divided into 2 groups: (1) conventional treatment group (C group, n = 130) and (2) conventional treatment plus lower-molecular weight heparin treatment group (LT group, n = 135). The clinical parameters, laboratory parameters and computed tomographic (CT) score of pancreatic necrosis (CTSPN), incidence of PE, and mortality in the 2 groups were compared. RESULTS: On admission, all the clinical parameters, laboratory parameters, and CTSPN in the 2 groups were not significantly different (P > 0.05). However, 1 to 2 weeks after treatment, the symptoms and signs improvement rate, the levels of blood and urine amylase, the CT score, and the Acute Physiology and Chronic Health Evaluation II score in the LT group were obviously lower than those in the C group (P < 0.05-0.01), and PE occurrence rate, mortality, and mean hospital stay in LT group were obviously lower than those in the C group (P < 0.05-0.01). CONCLUSIONS: Lower-molecular weight heparin can enhance the effect of conventional treatment of SAP and can markedly decrease the PE incidence and improve the survival rate of SAP. Lower-molecular weight heparin is a simple, safe, less expensive, and effective method for treatment of SAP. It can be used in every hospital.