ABSTRACT
MUC4, a transmembrane mucin, plays important roles in epithelial renewal and differentiation. Recent studies suggest that MUC4 has been implicated in pancreatic cancer pathogenesis and is expressed in various normal and cancer tissues. The underlying features of MUC4 across various cancer types may allow us to ensure appropriate treatment and patient monitoring. However, the contributions of MUC4 to pan-cancer have not been well characterized. In this study, we investigated the expression pattern and prognostic value of MUC4 across multiple databases. We further explored genomic and epigenetic alterations of MUC4, its association with proliferation and metastasis, and the correlation with immune infiltration in different cancers. Our results characterized the distinct expression profile and prognostic values of MUC4 in pan-cancer. Through examining its association with genomic alteration, tumor proliferation, and metastasis, as well as tumor infiltration, we revealed multiple function effects of MUC4. MUC4 may influence prognosis, proliferation, metastasis, and immune response in opposite directions. In conclusion, our findings suggested the necessity to more carefully evaluate MUC4 as a biomarker and therapeutic target and develop the new antibodies for cancer detection and intervention.
ABSTRACT
Sorafenib, an orally available kinase inhibitor, is the standard first-line systemic drug for advanced hepatocellular carcinoma (HCC), and it exerts potent inhibitory activity against epithelial-mesenchymal transition (EMT) and multidrug resistance (MDR) by inhibiting mitogen-activated protein kinase (MAPK) signaling in HCC. However, after long-term exposure to sorafenib, HCC cells exhibit EMT and resistance to sorafenib. The activation of AKT by sorafenib is thought to be responsible for the development of these characteristics. The present study aims to examine the underlying mechanism and seek potential strategies to reverse this resistance and the progression to EMT. Sorafenib-resistant cells showed increased metastatic and invasive ability, with a higher expression of P-glycoprotein (P-gp), compared with the parental cells. This phenomenon was at least partially due to EMT and the appearance of MDR in sorafenib-resistant HCC cells. Moreover, MDR was a downstream molecular event of EMT. Silencing Snail with siRNA blocked EMT and partially reversed the MDR, thereby markedly abolishing invasion and metastasis in sorafenib-resistant HCC cells, but silencing of MDR1 had no effect on the EMT phenotype. Additionally, HCC parental cells that were stably transfected with pCDNA3.1-Snail exhibited EMT and MDR. Two sorafenib-resistant HCC cell lines, established from human HCC HepG2 and Huh7 cells, were refractory to sorafenib-induced growth inhibition but were sensitive to MK-2206, a novel allosteric AKT inhibitor. Thus, the combination of sorafenib and MK-2206 led to significant reversion of the EMT phenotype and P-gp-mediated MDR by downregulating phosphorylated AKT. These findings underscore the significance of EMT, MDR and enhanced PI3K/AKT signaling in sorafenib-resistant HCC cells.
Subject(s)
Antineoplastic Agents/pharmacology , Carcinoma, Hepatocellular/enzymology , Drug Resistance, Neoplasm/physiology , Liver Neoplasms/enzymology , Niacinamide/analogs & derivatives , Phenylurea Compounds/pharmacology , Animals , Carcinoma, Hepatocellular/drug therapy , Cell Line, Tumor , Cell Movement/drug effects , Cell Movement/physiology , Cell Survival/drug effects , Cell Survival/physiology , Drug Resistance, Multiple/drug effects , Drug Resistance, Multiple/physiology , Epithelial-Mesenchymal Transition/drug effects , Epithelial-Mesenchymal Transition/physiology , Heterocyclic Compounds, 3-Ring/pharmacology , Humans , Liver Neoplasms/drug therapy , Male , Mice, Inbred BALB C , Mice, Nude , Neoplasm Invasiveness/physiopathology , Neoplasm Transplantation , Niacinamide/pharmacology , Phosphatidylinositol 3-Kinases/metabolism , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction/physiology , SorafenibABSTRACT
OBJECTIVE: To elucidate the chemical structures of the main antibacterial compound and red pigment produced by the co-culture of marine-derived fungus Aspergillus sp. SCSGAF 0076 and bacterium Bacillus sp. MNMCCE 001. METHODS: The monoculture of strain SCSGAF 0076 and co-culture of strains SCSGAF 0076 and MNMCCE 001 were done on amylum solid medium for three days, then the crude extracts of the cultures were obtained, and subsequently, the chemical profiles of the extracts of monoculture and co-culture were analyzed by HPLC. Using antibacterial bioassay-guided fractionation, we isolated the crude extract of the co-culture by silica gel column chromatogram, Sephadex LH-20, and semi-preparative HPLC to obtain the main antibacterial compound and red pigment. The compounds' structures were determined by spectroscopic analysis. RESULTS: We found that the main secondary metabolites produced by the monoculture of strain SCSGAF 0076 and co-culture of strains SCSGAF 0076 and MNMCCE 001 were almost the same, however, the contents of the main antibacterial compound and red pigment were obviously different. Totally, four compounds including the antibacterial compound penicillic acid, 5 (6) -dihydropenicillic acid, 9-chloro-8-hydroxy-8,9-deoxyasperlactone and red pigment viopurpurin were isolated from the crude extract of the co-culture medium. CONCLUSION: The main antibacterial compound of the co-culture of strains SCSGAF 0076 and MNMCCE 001 was penicillic acid, the main red pigment was viopurpurin, and the yields of the two compounds were proved by the co-culture.
