Caffeic acid phenethyl ester derivative exerts remarkable anti-hepatocellular carcinoma effect, non-inferior to sorafenib, in vivo analysis.

Caffeic acid phenethyl ester (CAPE) and its derivatives exhibit considerable effects against hepatocellular carcinoma (HCC), with unquestioned safety. Here we investigated CAPE derivative 1' (CAPE 1') monotherapy to HCC, compared with sorafenib. HCC Bel-7402 cells were treated with CAPE 1', the IC50 was detected using CCK-8 analysis, and acute toxicity testing (5 g/kg) was performed to evaluate safety. In vivo, tumor growth after CAPE 1' treatment was evaluated using an subcutaneous tumor xenograft model. Five groups were examined, with group 1 given vehicle solution, groups 2, 3, and 4 given CAPE 1' (20, 50, and 100 mg/kg/day, respectively), and group 5 given sorafenib (30 mg/kg/day). Tumor volume growth and tumor volume-to-weight ratio were calculated and statistically analyzed. An estimated IC50 was 5.6 µM. Acute toxicity tests revealed no animal death or visible adverse effects with dosage up to 5 g/kg. Compared to negative controls, CAPE 1' treatment led to significantly slower increases of tumor volume and tumor volume-to-weight. CAPE 1' and sorafenib exerted similar inhibitory effects on HCC tumors. CAPE 1' was non-inferior to sorafenib for HCC treatment, both in vitro and in vivo. It has great potential as a promising drug for HCC, based on effectiveness and safety profile.

Key Candidate Prognostic Biomarkers Correlated with Immune Infiltration in Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common subtype of primary liver cancer, which causes ~800,000 deaths annually world-wide. Immune checkpoint inhibitor (ICI) has reformed cancer therapy and achieved unprecedented results in various malignancies, including HCC. However, the response rate of immunotherapy is very low in HCC. Considereing the complicated and unique immune status in liver, we hypothesize that critical molecules will affect prognosis and correlate with immune context in the tumor microenvironment of HCC. METHODS: Using Kaplan-Meier plotter, GEPIA2 and Integrative Molecular Database of Hepatocellular Carcinoma (HCCDB), survival genes and their prognostic value were estimated in HCC. Based on Tumor Immune Estimation Resource (TIMER), association between survival genes and immune infiltration was examined in HCC. FunRich and STRING were used to analyze gene ontology and protein-protein interaction (PPI) Network, qRT-PCR was used to measure mRNA level of candidates; and a Cell Counting Kit-8 was used to measure proliferation of HCC cell line. RESULTS: Using multiple databases, we identified 36 key prognostic genes highly expressed in HCC and associated with poor survival of patients. Meanwhile, the 36 gene signatures correlated with immune infiltration in HCC. Moreover, these genes were significantly associated with exhausted T cells and polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in HCC. Among the 36 key genes, SKA3, SGOL2, SPINDOC, TEDC2, TMCO3 and NUP205 were highly expressed in tumor samples compared with adjacent normal tissues in our HCC cohort (n=22). Additionally, proliferation of SMMC7721 cell line was inhibited when it interfered with SiRNA of each gene. CONCLUSION: The 36 genes may serve as potential prognostic biomarkers and molecular targets to ameliorate tumor immune microenvironment (TIME) in HCC and therefore represent a novel avenue for individualized immunotherapy in HCC.

DNASE1L3 as a Prognostic Biomarker Associated with Immune Cell Infiltration in Cancer.

OBJECTIVES: Deoxyribonuclease 1 like 3 (DNASE1L3) is critically involved in apoptosis and immune response, however, its role in cancer has yet to be deciphered. We aimed to explore the prognostic value of DNASE1L3 across a series of malignancies. METHODS: Based on Oncomine database and Tumor Immune Estimation Resource (TIMER), expression profiling of DNASE1L3 was detailed in malignancies. Using PrognoScan, Kaplan-Meier Plotter, GEPIA2, and bc-GenEcMiner v4.5, prognostic value of DNASE1L3 was estimated in diverse cancers. Based on TIMER, association between DNASEL13 expression and immune infiltration was examined in various cancers. Then, mRNA level of DNASE1L3 in hepatocellular carcinoma (HCC) samples (n=22) and stomach adenocarcinoma (STAD) samples (n=17) was measured with qRT-PCR. Immunohistochemistry was performed to confirm expression of DNASE1L3 in paraffin-embedded tissues of HCC (n=9) and lung adenocarcinoma (n=20). RESULTS: DNASE1L3 was downregulated in multiple cancers, including breast invasive carcinoma (BRCA), cholangiocarcinoma (CHOL), liver hepatocellular carcinoma (LIHC), and lung adenocarcinoma (LUAD). A lower level of DNASE1L3 correlated with poorer prognosis in various cancers, especially in breast, liver, kidney, stomach, lung adenocarcinoma and sarcoma (SARC). Moreover, DNASE1L3 was positively related to immune cell infiltration in many cancers, including BRCA, LIHC, STAD, LUAD, and SARC. DNASE1L3 was significantly associated with CCR7/CCL19 in cancers. DNASE1L3 was downregulated in HCC and STAD tissues as demonstrated by qRT-PCR, as well as in HCC and LUAD samples, as shown by immunohistochemistry. CONCLUSION: DNASE1L3 has potential to serve as a prognostic biomarker in cancer of the breast, kidney, liver, stomach, lung adenocarcinoma and sarcoma. Down-regulation of DNASE1L3 may participate in immune escape via CCR7/CCL19 axis.

Erratum: The association between inflammation, the microbiome and urethane-induced pulmonary adenocarcinoma.

[This corrects the article DOI: 10.3892/ol.2018.8167.].

The association between inflammation, the microbiome and urethane-induced pulmonary adenocarcinoma.

Lung cancer is amongst the most common types of cancer throughout the world. The overall 5-year survival rate is ~17%. A number of studies have demonstrated that the microbiome existing within the host may affect the level of inflammation, and consequently contribute to the carcinogenesis of certain types of cancer. To investigate the role of inflammation and the microbiome in the carcinogenesis of lung cancer, an intervention study involving mice, including a control group (C; n=5), a urethane-induced pulmonary adenocarcinoma group (U; n=5) and a prebiotics intervention group (P; n=5) was carried out. This pulmonary adenocarcinoma model was reviewed, and incidences of the disease were identified using histopathology. The levels of the inflammatory cytokines nuclear factor κB (NF-κB), tumor necrosis factor α (TNF-α), interleukin-1ß (IL-1ß) and IL-6 in the sera samples were measured using an ELISA technique. In addition, high-throughput sequencing of the 16S ribosomal RNA gene segment was used to analyze the species present in the microbiome of the lower airways and intestinal tracts of mice. The results demonstrated that groups P and U exhibited altered histopathology and the development of lung adenocarcinoma tumors, but no differences were observed between the groups. The level of inflammation, determined by measuring the levels of NF-κB, TNF-α, IL-1ß and IL-6 inflammatory cytokines, was significantly lower in group P compared with group U (P<0.05), and was significantly higher in group P compared with group C (P<0.05). Overall, the microbiomes of the lower respiratory and intestinal tracts did not change markedly among the 3 groups, in terms of the size of colonies and Shannon diversity indices. However, at a family and operational taxonomic unit (OTU) level, certain microbiota were altered. For example, the abundance of the Clostridiales and Lachnospiraceae families was lower in the lung and intestinal tracts subsequent to urethane-induced treatment compared with in the control group (P<0.05), and the level of abundance of the Clostridiales family increased to similar levels within the control group (P<0.05), when prebiotics were administered. The levels of abundance of the S24-7, Bacteroidales and Firmicutes families were higher in the intestinal tract compared with the control group (P<0.05), and following treatment with prebiotics, the levels of abundance of these families decreased to similar levels observed in the control group (P<0.05). In conclusion, inflammation and the microbiome serve important roles in the carcinogenesis of lung cancer. Additionally, prebiotics may increase the efficacy of lung cancer treatment by modulating levels of inflammation and the composition of the microbiome. The associations between inflammation, the microbiome and lung cancer require attention.