Prostate cancer (PCa) is a major health problem in males. Metastasis-associated with lung adenocarcinoma transcript-1 (MALAT1), which is overexpressed in PCa tissue, is associated with physiological and pathological conditions of PCa. M2 macrophages are major immune cells abundant in the tumor microenvironment. However, it remains unknown whether M2 macrophages are involved in the effects or not, and molecular mechanisms of MALAT1 on PCa progression have not yet been comprehensively explored. Here we reported that, M2 macrophages (PMA/IL-4 treated THP1) induced MALAT1 expression in PCa cell lines. Knockdown MALAT1 expression level in PCa cell lines inhibited cellular proliferation, invasion, and tumor formation. Further mechanistic dissection revealed that M2 macrophages secreted IL-8 was sufficient to drive up MALAT1 expression level via activating STAT3 signaling pathway. Additional chromatin immunoprecipitation (ChIP) and luciferase reporter assays displayed that STAT3 could bind to the MALAT1 promoter region and transcriptionally stimulate the MALAT1 expression. In summary, our present study identified the IL-8/STAT3/MALAT1 axis as key regulators during prostate tumorigenesis and therefore demonstrated a new mechanism for the MALAT1 transcriptional regulation.
Disulfidptosis, a new form of cell death triggered by disulfide stress, is characterized by the collapse of cytoskeleton proteins and F-actin due to the intracellular accumulation of disulfides. This discovery will eventually aid in the development of therapeutic strategies against cancer.
Establishing latent infection but retaining the capability to reactivate in certain circumstance is an ingenious tactic for retroviruses to persist in vivo while evading host immune surveillance. Many evidences indicate that Human T-cell leukemia virus type 1 (HTLV-1) is not completely silent in vivo . However, signals that trigger HTLV-1 latency-reactivation switching remain poorly understood. Here, we show that aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, plays a critical role in HTLV-1 plus-strand expression. Importantly, HTLV-1 reactivation could be tunably manipulated by modulating the level of AHR ligands. Mechanistically, activated AHR binds to HTLV-1 LTR dioxin response element (DRE) site (CACGCATAT) and drives plus-strand transcription. On the other hand, persistent activation of nuclear factor kappa B (NF-κB) pathway constitutes one key prerequisite for AHR overexpression in HTLV-1 infected T-cells, setting the stage for the advent of AHR signaling. Our findings suggest that HTLV-1 might achieve its reactivation in vivo when encountering environmental, dietary, microbial and metabolic cues that induce sufficient AHR signaling.
Purpose: To investigate the effects of BEZ235 on chronic myeloid leukemia (CML) cells. Methods: MTS assay was used to detect the proliferation of CML cells. The proteins expression were detected by Western blot assay. The effects of BEZ235 on autophagy in CML cells were verified through transmission electron microscopy and evaluated by laser confocal microscopy. Annexin V-FITC/PI double staining flow cytometry was used to detect apoptosis. A xenograft model was established to observe the therapeutic effect of BEZ235 in vivo. Results: BEZ235 could inhibit the proliferation of CML cells; CQ and 3-MA could increase the proliferation inhibition and Z-VAD-FMK can reduce the proliferation inhibition of BEZ235 on CML cells (P<0.05). Results of TEM showed that the autophagosomes of CML cells treated with BEZ235 increased (P<0.05). The results by confocal microscopy showed that the autophagic activity of K562 cells increased with BEZ235 treatment. When BEZ235 combined with CQ, BEZ235-induced autophagic flow was blocked. FCM results showed that BEZ235 could induces apoptosis in CML cells. Z-VAD-FMK could decrease the apoptosis of CML cells induced by BEZ235. CQ increased the apoptosis of CML cells induced by BEZ235 (P<0.05). Western blot showed that BEZ235 inhibited the phosphorylation of AKT and S6K. BEZ235 alone could upregulate the expression of cleaved caspase-3 and LC3II. When combined with Z-VAD-FMK, the expression of cleaved caspase-3 was lower than that of BEZ235 alone. When combined with CQ, the expression of cleaved caspase-3 and LC3II were higher than those of BEZ235 alone (P<0.05). BEZ235 could inhibit the growth of xenografts of CML cell line. Conclusion: BEZ235 can inhibit the proliferation of CML cells, induce apoptosis, and enhance autophagy activity. It induces protective autophagy. The combination of CQ can enhance the apoptosis and proliferation inhibition of CML cells induced by BEZ235.
Background. Cancerous embryo antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) are commonly used in clinical practice to assist in diagnosing CRC. However, their sensitivity is very low. This study aims to investigate the clinical significance of circulating tumor cells (CTCs) and circulating tumor endothelial cells (CTECs) compared with CEA and CA19-9 in the auxiliary diagnosis of colorectal cancer (CRC) patients. Methods. 115 pathologically confirmed CRC patients and 20 healthy controls were enrolled in this study. CTCs and CTECs were enriched and identified by subtraction enrichment and immunostaining-fluorescence in situ hybridization (SE-iFISH). A logistic regression was used to establish a model for the receiver-operating characteristic (ROC) curve analysis, and the diagnostic efficacy of CTCs, CTECs, CEA, CA19-9, and their combinations was analyzed. Results. The CTC ( P < 0.0001 ) and CTEC ( P = 0.0009 ) level was significantly higher in CRC patients than that in healthy controls. For CRC patients, CTC and CTEC level was significantly correlated with tumor stage and lymph node metastasis status, but not with sex, age, tumor location, and degree of differentiation. The positive rate of CTCs, CTECs, CEA, and CA19-9 in CRC patients was 87.8%, 39.1%, 28.7%, and 26.1%, respectively. To distinguish CRC patients from controls, the area under the curve (AUC) of CTC was 0.889, which was much higher than 0.695 of CTEC, 0.696 of CEA, and 0.695 of CA19-9. Establishing ROC curve by logistic regression algorithm, the highest AUC was 0.935, which combined CTCs with CTEC, CEA, and CA19-9. Conclusions. CTCs combined with CTEC, CEA, and CA19-9 are useful to improve the diagnostic efficiency, which has high clinical significance in the diagnosis of colorectal cancer.
BackgroundBoth cancer and diabetes are complex chronic diseases that have high economic costs for society. The co-occurrence of these two diseases in people is already well known. The causal effects of diabetes on the development of several malignancies have been established, but the reverse causation of these two diseases (e.g., what type of cancer can cause T2D) has been less investigated.MethodsMultiple Mendelian randomization (MR) methods, such as the inverse-variance weighted (IVW) method, weighted median method, MR-Egger, and MR pleiotropy residual sum and outlier test, were performed to evaluate the causal association of overall and eight site-specific cancers with diabetes risk using genome-wide association study summary data from different consortia, such as Finngen and UK biobank.ResultsA suggestive level of evidence was observed for the causal association between lymphoid leukaemia and diabetes by using the IVW method in MR analyses (P = 0.033), indicating that lymphoid leukaemia increased diabetes risk with an odds ratio of 1.008 (95% confidence interval, 1.001-1.014). Sensitivity analyses using MR-Egger and weighted median methods showed consistent direction of the association compared with the IVW method. Overall and seven other site-specific cancers under investigation (i.e., multiple myeloma, non-Hodgkin lymphoma, and cancer of bladder, brain, stomach, lung, and pancreas) were not causally associated with diabetes risk.ConclusionsThe causal relationship between lymphoid leukaemia and diabetes risk points to the necessity of diabetes prevention amongst leukaemia survivors as a strategy for ameliorating the associated disease burden.
Potentiometric immunoassays have been utilized for the quantitative detection of alpha-fetoprotein (AFP) in hepatocellular carcinoma, but most involve low sensitivity and enzyme labels, and thus are unfavorable for routine use....
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