MicroRNA-219-5p Promotes Tumor Growth and Metastasis of Hepatocellular Carcinoma by Regulating Cadherin 1.

MicroRNAs play significant roles in the development of cancer and may serve as promising therapeutic targets. In our previous work, miR-219-5p was identified as one of the important metastasis-related microRNAs in HCC. Here we demonstrated that miR-219-5p expression was elevated in HCC tissues and was associated with vascular invasion and dismal prognosis. In multivariate analysis, miR-219-5p was identified as an independent prognostic indicator for HCC patients. Functional mechanism analyses showed that miR-219-5p promoted HCC cell proliferation and invasion in in vitro, as well as in vivo, tumor growth and metastasis in nude mice models bearing human HCC tumors. In addition, cadherin 1 (CDH1) was revealed to be a downstream target of miR-219-5p in HCC cells. In conclusion, miR-219-5p promotes tumor growth and metastasis of HCC by regulating CDH1 and can serve as a prognostic marker for HCC patients.

Osteopontin promotes metastasis of intrahepatic cholangiocarcinoma through recruiting MAPK1 and mediating Ser675 phosphorylation of ß-Catenin.

The incidence and mortality of intrahepatic cholangiocarcinoma (ICC) are increasing worldwide in recent decades. Osteopontin (OPN) plays an important role in cancer metastasis, but its functional mechanism in ICC is not clear yet. In this study, we found that OPN level was elevated both in plasma and tumor tissues of ICC patients, which was closely related to a shorter overall survival (OS) and high probability of tumor relapse after curative resection. The gain- and loss-of-function studies determined that OPN could promote ICC growth and metastasis. OPN selectively interacted with ß-Catenin and knockdown of ß-Catenin abrogated the effects induced by OPN. OPN recruited MAPK1 and activated MEK-MAPK1 pathway to mediate the S675 phosphorylation of ß-Catenin and nucleus accumulation, which induced the activation of Wnt signaling. Moreover, a significant correlation between OPN and ß-Catenin was found in ICC tissues. OPN, ß-Catenin, and their combination were independent prognostic indicator for ICC patients. In conclusion, OPN promotes ICC progression through recruiting MAPK1 and activating the Wnt/ß-Catenin pathway and can serve as a novel prognostic marker and therapeutic target for ICC.

Whole-exome mutational and transcriptional landscapes of combined hepatocellular cholangiocarcinoma and intrahepatic cholangiocarcinoma reveal molecular diversity.

BACKGROUND: Primary liver cancer (PLC) is the third largest contributor to cancer mortality in the world. PLC is a heterogeneous disease that encompasses several biologically distinct subtypes including hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC) and combined hepatocellular-cholangiocarcinoma (CHC). CHC is a distinct, albeit rare, subtype of PLC and is comprised of cells with histopathological features of both HCC and ICC. Several studies have focused on the mutation and expression landscapes of HCC and ICC. However, studies of CHC were rare. OBJECTIVE: The aim of the current study was to identify genetic and gene expression alterations in the carcinogenesis and development of CHC and ICC in the Chinese population. Unraveling both similar and differing patterns among these subtypes may help to identify personalized medicine approaches that could improve patient survival. METHODS: Whole genome sequencing (WGS), whole exome sequencing (WES) and RNA-seq were performed on 10 ICC and 10 CHC samples, matched with adjacent non-tumor liver tissue specimens. Comparative analysis was performed using HCC datasets from The Cancer Genome Atlas (TCGA). RESULTS: Mutational and transcriptional landscapes of CHC and ICC were clearly delineated. TP53 and CTNNB1 were identified as exhibiting mutations in CHC. ARID1A, PBRM1, and IDH1 were frequently mutated in ICC. RYR3, FBN2, and KCNN3 are associated with cell migration and metastasis and might be driver genes in CHC. KCNN3 was identified as also exhibiting mutations in ICC. The ECM-receptor interaction pathway associated fibrogenic hepatic progenitor cell differentiation and liver fibrosis may play an important role in carcinogenesis of PLC. Chromatin remodeling and chromosome organization are key processes in carcinogenesis and development in PLC. P53 related pathways showed alterations in CHC and HCC. Inflammation may be a key factor involved in ICC carcinogenesis. CONCLUSION: CHC and ICC are different subtypes of PLC. This study discusses predominantly the molecular genetic details of PLC subtypes and highlights the need for an accurate diagnosis and treatment of specific PLC subtypes to optimize patient management.

Efficacy of salmeterol fluticasone propionate combined with montelukast in the treatment of moderate and severe bronchial asthma / 中国生化药物杂志

Objective To investigate the clinical effect of salmeterol fluticasone propionate combined with montelukast in the treatment of moderate and severe bronchial asthma. Methods 112 patients with moderate and severe bronchial asthma in Taizhou hospital from January 2014 to December 2016 were selected and divided into the control and the study group according to the time of visiting hospital, 56 cases in each group. The control group were given salmeterol fluticasone propionate for treatment, the study group were treated with salmeterol fluticasone propionate combined with montelukast .Keep a record of the asthma control test (ACT), forced expiratory volume (FEV1) percentage expected index changes of pre-treatment and 8 weeks after treatment. Results ACT score and FEV1 percentage expected index changes of two groups there was no significant difference before the treatment. After treatment, ACT score and FEV1 percentage expected index changes of the study group was better than the control group(P<0.05). Conclusion Salmeterol fluticasone propionate combined with montelukast in the treatment can significantly improve the clinical efficacy of patients.

Efficacy of salmeterol fluticasone propionate combined with montelukast in the treatment of moderate and severe bronchial asthma / 中国生化药物杂志

Objective To investigate the clinical effect of salmeterol fluticasone propionate combined with montelukast in the treatment of moderate and severe bronchial asthma. Methods 112 patients with moderate and severe bronchial asthma in Taizhou hospital from January 2014 to December 2016 were selected and divided into the control and the study group according to the time of visiting hospital, 56 cases in each group. The control group were given salmeterol fluticasone propionate for treatment, the study group were treated with salmeterol fluticasone propionate combined with montelukast .Keep a record of the asthma control test (ACT), forced expiratory volume (FEV1) percentage expected index changes of pre-treatment and 8 weeks after treatment. Results ACT score and FEV1 percentage expected index changes of two groups there was no significant difference before the treatment. After treatment, ACT score and FEV1 percentage expected index changes of the study group was better than the control group(P<0.05). Conclusion Salmeterol fluticasone propionate combined with montelukast in the treatment can significantly improve the clinical efficacy of patients.

Interleukin-6 enhances cancer stemness and promotes metastasis of hepatocellular carcinoma via up-regulating osteopontin expression.

Interleukin-6 (IL-6), one of the most important inflammatory cytokines, plays a pivotal role in metastasis and stemness of solid tumors. However, the underlying mechanisms of IL-6 in HCC metastasis remain unclear. In the present study, we demonstrated that stemness and metastatic potential of HCC cells were significantly enhanced after IL-6 stimulation. IL-6 could induce expression of osteopontin (OPN), along with other stemness-related genes, including HIF1α, BMI1, and HEY1. Block of OPN induction could significantly abrogate the effect of IL-6 on stemness and metastasis of HCC cells. Furthermore, IL-6 level was positively correlated with OPN in HCC. Patients with high plasma IL-6 or OPN level had poorer prognosis. In multivariate analysis, IL-6 and OPN were demonstrated to be independent prognostic indicators for HCC patients, and their combination had a better prognostic performance than IL-6 or OPN alone. Collectively, our findings indicate that IL-6 could enhance stemness and promote metastasis of HCC via up-regulating OPN expression, which can be a potential therapeutic target for combating HCC metastasis, and the combination of IL-6 and OPN serves as a promising prognostic predictor for HCC.

ß-catenin mutation is correlated with a favorable prognosis in patients with hepatocellular carcinoma.

The ß-catenin gene is frequently mutated in patients with hepatocellular carcinoma (HCC) and has long been thought to be one of the major oncogenes involved in the hepatocarcinogenesis. The prognostic role of ß-catenin mutation in HCC remains unclear. To address this issue, a search for relevant studies was performed in the PubMed, Embase and Web of Science databases. The pooled effect was calculated from the available data to evaluate the correlation of ß-catenin mutation with overall survival rate and tumor clinicopathological features in patients with HCC. The pooled odds ratio (OR) was calculated using the Mantel-Haenszel model for fixed effects. Three studies met the inclusion criteria. A total of 618 cases were included, and ß-catenin mutation was identified in 104 of them. The meta-analysis revealed that the presence of ß-catenin mutation (n=104), compared with the control group (n=514), was correlated with a longer overall survival rate [OR, 0.33; 95% confidence interval (CI), 0.21-0.53; P<0.00001] in patients with HCC. No significant heterogeneity was found among the eligible studies (I2=0%; P=0.72). ß-catenin mutation was correlated with a relatively lower rate of hepatitis B virus infection (OR, 0.36; 95% CI, 0.21-0.61; P=0.0002), improved tumor differentiation (OR, 0.32; 95% CI, 0.19-0.56; P<0.0001) and a lower tumor-node-metastasis stage (I+II) (OR, 0.23; 95% CI, 0.14-0.38; P<0.00001). These findings suggest that ß-catenin mutation may predict a favorable prognosis in patients with HCC.

MicroRNA-26a suppresses tumor growth and metastasis of human hepatocellular carcinoma by targeting interleukin-6-Stat3 pathway.

UNLABELLED: Down-regulation of microRNA-26a (miR-26a) is associated with poor prognosis of hepatocellular carcinoma (HCC), but its functional mechanism in HCC remains unclear. In this study, we investigated the roles of miR-26a in tumor growth and metastasis of HCC and found that miR-26a was frequently down-regulated in HCC tissues. Down-regulation of miR-26a correlated with HCC recurrence and metastasis. Through gain- and loss-of-function studies, miR-26a was demonstrated to significantly inhibit in vitro cell proliferation, migration, and invasion. In addition, miR-26a induced G1 arrest and promoted apoptosis of HCC cells. Importantly, miR-26a suppressed in vivo tumor growth and metastasis in nude mice models bearing human HCC. Interleukin-6 (IL-6) was identified as a target of miR-26a. Knockdown of IL-6 induced effects on HCC cells similar to those induced by miR-26a. In contrast, IL-6 treatment abrogated the effects induced by miR-26a up-regulation. Moreover, miR-26a dramatically suppressed expression of signal transducer and activator of transcription 3 (Stat3) target genes, including Bcl-2, Mcl-1, cyclin D1, and MMP2. IL-6 treatment antagonized this effect, while knockdown of IL-6 by IL-6 short hairpin RNA (shIL-6) induced inhibitory effects on the expression of p-Stat3 and its main target genes, similar to miR-26a. The messenger RNA and protein levels of IL-6 inversely correlated with miR-26a in HCCs. Patients with high miR-26a or low IL-6 in HCC tissues had a better prognosis with longer overall survival (OS) and time to recurrence (TTR). In multivariate analysis, miR-26a, IL-6, and their combination were demonstrated to be independent prognostic indicators for OS and TTR of HCC patients. CONCLUSION: miR-26a could suppress tumor growth and metastasis of HCC through IL-6-Stat3 signaling and is a novel prognostic marker and therapeutic target for HCC.

MicroRNA-29a-5p is a novel predictor for early recurrence of hepatitis B virus-related hepatocellular carcinoma after surgical resection.

It is still difficult to predict the probability of tumor recurrence after resection of hepatocellular carcinoma (HCC). In this study, we set out to identify specific microRNA (miRNA) in microdissected hepatitis B virus (HBV)-related HCC tissue from formalin-fixed paraffin-embedded (FFPE) samples which might be used in predicting early recurrence after HCC resection. Taqman low density arrays were used to detect the 667 miRNA profiles in both the microdissected tumorous and adjacent non-tumorous liver tissues from 20 HCC patients (discovery set) including 10 patients with early tumor recurrence and 10 without early tumor recurrence and to identify the differentially expressed miRNAs related to HCC recurrence. Then quantitative real-time PCR (qRT-PCR) was used to verify the findings in 106 patients (training set), and to develop a predictive assay. The identified miRNAs were further validated in an independent cohort of 112 patients (validation set). Thirty seven miRNAs were identified from 20 HCC patients and validated in 106 HCC patients using qRT-PCR. A significant association was found between miR-29a-5p level in HCC tissues and early tumor recurrence (P = 0.0002). This association was further confirmed in the independent validation set of 112 patients (P = 0.0154). MiR-29a-5p level was significantly associated with both time to tumor recurrence (TTR) (P = 0.0015) and overall survival (OS) (P = 0.0079) in validation set. In the multivariate analyses, miR-29a-5p was identified as an independent factor for TTR, particularly for those patients with early stage of HCC. The sensitivity and specificity of miR-29a-5p for the prediction of early HCC recurrence of BCLC 0/A stage HCC were 74.2% and 68.2%, respectively. These suggest that miR-29a-5p might be a useful marker for the prediction of early tumor recurrence after HCC resection, especially in BCLC 0/A stage HCCs.

Association of specific genotypes in metastatic suppressor HTPAP with tumor metastasis and clinical prognosis in hepatocellular carcinoma.

The phosphatidic acid phosphatase HTPAP has been defined as a metastatic suppressor of hepatocellular carcinoma (HCC), but little is known about its function or potential applications as a prognostic marker. In this study, we analyzed patterns of HTPAP genetic variation and gene expression in 864 patients who underwent HCC resection, assessing these patterns for correlations to tumor metastasis potential. Focusing on two tagSNPs that were selected (+357G/C and +1838A/G), we found that only the +357G/C genotype was significantly associated with HTPAP mRNA and protein expression levels and the probability of metastasis. In an independent cohort of 665 HCC patients, we determined that the +357G/C genotype was associated with shorter time to recurrence and overall survival. Together, these results indicated that the HTPAP tagSNP +357 GG+GC genotypes may influence HCC metastatic potential and clinical prognosis by down-regulating HTPAP expression. Extending these results, a global expression profiling analysis identified 41 genes including the pro-inflammatory genes IL-8 and TLR2 that were significantly overexpressed in the +357 GG+GC group, as possible coregulated markers with HTPAP. Together, our findings identify an HTPAP genotype and associated gene expression pattern that favors metastasis progression and that could be used to predict tumor metastasis and prognosis in HCC patients.