The effects of REG4 expression on chemoresistance of ovarian cancer.

Although ovarian cancer usually responds well to platinum- and taxane-based first-line chemotherapy, most patients develop recurrence and chemoresistance. Regenerating gene 4 (REG4) is a secretory protein involved in cell differentiation and proliferation. We found higher REG4 expression in ovarian cancer than in normal tissues (p < .05). Regenerating gene 4 expression was negatively associated with overall, progression-free or post-progression survival rates of patients with ovarian cancer receiving platinum or paclitaxel treatment (p < .05) according to a Kaplan-Meier plotter. Regenerating gene 4 overexpression resulted in either cisplatin or paclitaxel resistance, and apoptosis resistance in CAOV3 ovarian cancer cells (p < .05). REG4-transfected ovarian cancer cells showed stronger migration and invasion treated with cisplatin or paclitaxel (p < .05). Additionally, cisplatin or paclitaxel exposure led to the overexpression of phosphorylated phosphoinositide 3-kinase (p-PI3K), p-Akt, phosphorylated mammalian target of rapamycin (p-mTOR), glutathione S-transferase-π, survivin, and B-cell lymphoma 2 in REG4 transfectants compared with control cells (p < .05). These findings suggested that REG4 expression was up-regulated in ovarian cancer, and associated with poor survival and chemotherapy resistance. REG4 promoted the occurrence, development, and chemotherapy resistance of ovarian cancer by regulating cell proliferation, apoptosis, migration, and invasion, and PI3K/Akt/m-TOR signalling pathways. IMPACT STATEMENTWhat is already known on this subject? REG4 mRNA expression is up-regulated in many digestive cancers. High REG4 expression was associated with an adverse prognosis, high tumour and nodal stages, poor differentiation, and hepatic and peritoneal metastases of digestive cancers. REG4 expression conferred cancer cells with increased resistance to chemoradiotherapy, especially 5-FU-based treatment, by activating the MAPK/Erk/Bim signalling pathway.What do the results of this study add? REG4 was highly expressed in ovarian cancer. The expression of p-PI3K, p-AKT, p-mTOR, GST-π, survivin, and Bcl-2 was increased in REG4-overexpressing cells. High REG4 expression was significantly associated with inferior OS, PFS, and PPS rates in patients with ovarian cancer receiving platinum chemotherapy. REG4 mediated cisplatin and paclitaxel resistance in CAOV3 ovarian cancer cells. The percentage of apoptotic cells was markedly lower in REG4-transfected compared to mock-transfected cells after cisplatin or paclitaxel treatment.What are the implications of these findings for clinical practice and/or further research? This study aimed to evaluate the prognostic significance of REG4 expression in ovarian cancer treated with platinum and paclitaxel, to explore REG4 chemoresistance mechanisms to platinum and paclitaxel, and to provide a scientific experimental basis for the clinical treatment and outcome evaluation of ovarian cancer. In order to provide comprehensive clinical treatment of ovarian cancer, it is helpful to improve our understanding of multi-drug resistance and identify new cancer diagnostic biomarkers.

The clinicopathological and prognostic significances of LATS1 expression in breast cancer.

AIM: Large tumor suppressor gene 1 (LATS1) belongs to the PKA/PKG/PKC serine/threonine kinase subfamily of the Hippo signaling pathway and inactivates nuclear co-activators YAP1 and WWTR1 by phosphorylation. This study aimed to discern the clinicopathological and prognostic significances of LATS1 expression in breast cancer. METHODS: We examined LATS1 expression in breast carcinogenesis and compared it with clinicopathological parameters and survival information of breast cancer patients using immunohistochemistry, western blotting, RT-PCR, and bioinformatics analysis. RESULTS: LATS1 expression was downregulated in breast cancer at both mRNA and protein levels (P<0.05). LATS1 mRNA expression was negatively correlated with low ER and PR expression, aggressive subtypes (TNBC and HER2+ vs. luminal), and poor survival (P<0.05). Its protein expression was negatively linked to patient age, T stage, N stage, M stage histological grade, PR status, and unfavorable prognosis (P<0.05). There was a positive correlationship between nuclar and cytoplasmic LATS1 expression in breast cancer (P<0.05). CONCLUSIONS: The downregulation of LATS1 expression plays a vital role in the carcinogenesis and progression of breast cancer. Thus, LATS1 loss was employed to indicate the aggressive behaviors and poor prognosis of breast cancer.

Inhibition of chaperone­mediated autophagy reduces tumor growth and metastasis and promotes drug sensitivity in colorectal cancer.

Chaperone­mediated autophagy (CMA) is a selective type of autophagy whereby a specific subset of intracellular proteins is targeted to the lysosome for degradation. The present study investigated the mechanisms underlying the response and resistance to 5­fluorouracil (5­FU) in colorectal cancer (CRC) cell lines. In engineered 5­FU­resistant CRC cell lines, a significant elevation of lysosome­associated membrane protein 2A (LAMP2A), which is the key molecule in the CMA pathway, was identified. High expression of LAMP2A was found to be responsible for 5­FU resistance and to enhance PLD2 expression through the activation of NF­κB pathway. Accordingly, loss or gain of function of LAMP2A in 5­FU­resistant CRC cells rendered them sensitive or resistant to 5­FU, respectively. Taken together, the results of the present study suggested that chemoresistance in patients with CRC may be mediated by enhancing CMA. Thus, CMA is a promising predictor of chemosensitivity to 5­FU treatment and anti­CMA therapy may be a novel therapeutic option for patients with CRC.

[FGF21 inhibits lipid accumulation and inflammation induced by palmitate in human hepatocytes via SIRT1 pathway].

Objective To investigate the effect of fibroblast growth factor 21 (FGF21) on the lipid accumulation and inflammation induced by palmitate treatment in L02 hepatocytes and the underlying mechanism. Methods L02 cells were infected with lentivirus expressing SIRT1 shRNA to knockdown SIRT1 expression. Wild-type and SIRT1-knockdown L02 cells were treated with 250 mol/L palmitate for 5 days, and then administrated with 1 g/ml FGF21 for 72 hours. Triglycerides in the cells were detected with the infinity triglycerides reagent. Malondialdehyde (MDA) in the cells was assessed by MDA detection assay. Tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) levels in supernatant were measured by ELISA. Reactive oxygen species (ROS) levels were tested by the specific Amplex red ROS detection assay kit from Thermo Fisher Company. The gene expression of SIRT1, peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α), superoxide dismutase 2 (SOD2) and catalase (CAT) were measured by real-time quantitative PCR. The protein levels of SIRT1, PGC1α, SOD2 and CAT were detected by Western blot analysis. Mitochondrial membrane potentials were detected by the JC-1staining kit. Mitochondrial oxygen consumption rate (OCR) was detected with the Seahorse XF Mito stress test kit. Results Palmitate increased the triglycerides level, induced the oxidative stress in both the cells and the mitochondria, decreased the gene expression and protein levels of SIRT1, PGC1α, SOD2 and CAT, increased the levels of TNF-α and IL-6, decreased the mitochondrial membrane potential, and impaired the mitochondrial function. FGF21 treatment could attenuate all of these effects caused by palmitate, while SIRT1 knockdown blocked most of the FGF21 effects on the L02 hepatocytes. Conclusion FGF21 activates SIRT1 pathway and inhibites the lipid accumulation, improves the mitochondrial function, and decreases the oxidative stress as well as inflammation in palmitate-treated L02 cells.

The characterization and prognostic significance of right ventricular glucose metabolism in non-ischemic dilated cardiomyopathy.

AIMS: In dilated cardiomyopathy (DCM), there are limited data on right ventricular (RV) glucose metabolism assessed by [(18)F]fludeoxyglucose positron emission tomography ((18)F-FDG PET) imaging. We aimed to characterize RV glucose metabolism and investigate the prognostic significance of RV FDG uptake in DCM. METHODS AND RESULTS: (18)F-FDG PET imaging and cardiac magnetic resonance imaging (MRI) were performed in 63 consecutive DCM patients within an interval of 3-7 days. There was a significant correlation between RVEF and RV FDG uptake whether corrected RV standard uptake value (cRVSUV) (r = -0.571, P < .001) or the relative RV FDG uptake determined as the ratio of RV to left ventricular (LV) corrected SUV (cR/L) (r = -0.405, P < .001) was used. During a median follow-up period of 804 days, 15 patients (23.8%) reached the primary endpoint of all-cause mortality or heart transplantation. On univariate Cox analysis, cRVSUV > 7.01 and cR/L > 0.795 were significantly associated with the overall survival (hazard ratio [HR] 5.415, 95% confidence interval [CI] 1.945-15.078, P < .001; HR 6.422, 95% CI 2.250-18.332, P < .001). Patients with increased RV FDG uptake had a worse outcome (cRVSUV > 7.01 vs cRVSUV ≤ 7.01, log-rank 13.085, P < .001; cR/L > 0.795 vs cR/L ≤ 0.795, log-rank 15.695, P < .001). On multivariate analysis, cR/L > 0.795 remained a significant independent predictor of the endpoint (HR 5.001, 95% CI 1.641-15.239, P = .004), while cRVSUV > 7.01 showed no significance (HR 2.611; 95% CI 0.797-8.558; P = .113). CONCLUSIONS: Increased RV FDG uptake was associated with RV dysfunction and may be a prognostic predictor of all-cause mortality or heart transplantation in patients with DCM.