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•SFI administration was sufficient to alleviate the depressive-like behaviors of tumor-bearing mice.•SFI might inhibit pro-inflammatory cytokines produced by peripheral immune ...cells.•SFI might relieve fatigue symptoms by restraining the dysfunction of exhausted T cells.•SFI might improve the immunity of tumor-bearing mice through the targets of PDL1, TIM3 and FOXP3.
Cancer-related fatigue (CRF) not only has a negative impact on work, daily activities and social relationships, but also be a predictor of cancer patients' survival. And it has no FDA-approved therapy. ShenQi FuZheng Injection (SFI) is clinically used for adjuvant treatment of lung cancer and gastric cancer. And we found that SFI can improve the incidence of CRF in patients with gastric cancer. However, its efficacy against CRF remains to be elucidated. In the present study we established a tumor-bearing mouse fatigue model, conducted the forced swim test (FST) and grip strength measurements to evaluate the therapeutic effect of SFI. Additionally, we detected inflammation and immune indicators. The result showed that SFI administration could reduce depressive-like behaviors in tumor-bearing mice and inhibit tumor growth. In addition, SFI might improve fatigue symptoms by inhibiting pro-inflammatory cytokines produced by peripheral immune cells, restrain the dysfunction of exhausted T cells and improve the anti-tumor immunity through the targets of PDL1, TIM3 and FOXP3. These data suggested that SFI might be useful in alleviating CRF and provide further support to confirm SFI as a potential therapy for CRF in humans.
Despite the optimization of diagnostic and therapeutic strategy for HCC treatment, the prognosis has not been markedly improved 3. ...elucidating tumor-specific mechanisms for HCC onset and ...progression is essential for identifying novel therapeutic targets and developing therapeutic strategies. In 2011, Salmena et al. put forward a ceRNA hypothesis, that is, mRNAs, lncRNAs and other ncRNAs share common miRNA response elements (MREs), thus restraining miRNA biological function by competitively binding with MREs on the target mRNA 5. ...lncRNAs and mRNAs may act as potential diagnostic and prognostic biomarkers for HCC due to their good specificity and accessibility. ...lncRNA TUG1 binding the same 3′-UTR site of hsa-miR-328-3p with SRSF9 mRNA was screened by miRanda, and its expression trend in HCC tissues and the adjacent non-cancerous liver tissues was also similar to that of SRSF9 mRNA. ...the dual-luciferase reporter gene assay validated that both SRSF9 mRNA and lncRNA TUG1 were the targets of hsa-miR-328-3p with the same binding site (Additional file 1: ...the occurrence of SRSF9 mRNA and lncRNA TUG1 overexpression in male HCC patients was both more frequent than that in female.
Artesunate (ART) has been indicated as a candidate drug for hepatocellular carcinoma (HCC). Glucosylceramidase (GBA) is required for autophagic degradation. Whether ART regulates autophagic flux by ...targeting GBA in HCC remains to be defined. Herein, our data demonstrated that the dramatic overexpression of GBA was significantly associated with aggressive progression and short overall survival times in HCC. Subsequent experiments revealed an association between autophagic activity and GBA expression in clinical HCC samples, tumor tissues from a rat model of inflammation-induced HCC and an orthotopic mouse model, and human HCC cell lines. Interestingly, probe labeling identified GBA as an ART target, which was further verified by both a glutathione-S-transferase pulldown assay and surface plasmon resonance analysis. The elevated protein expression of LC3B, the increased numbers of GFP-LC3B puncta and double-membrane vacuoles, and the enhanced expression of SQSTM1/p62 indicated that the degradation of autophagosomes in HCC cells was inhibited by ART treatment. Both the in vitro and in vivo data revealed that autophagosome accumulation through targeting of GBA was responsible for the anti-HCC effects of ART. In summary, this preclinical study identified GBA as one of the direct targets of ART, which may have promising potential to inhibit lysosomal autophagy for HCC therapy.
Metastatic castration-resistant prostate cancer (mCRPC) is a highly aggressive stage of prostate cancer, and non-mutational epigenetic reprogramming plays a critical role in its progression. Super ...enhancers (SE), epigenetic elements, are involved in multiple tumor-promoting signaling pathways. However, the SE-mediated mechanism in mCRPC remains unclear.
SE-associated genes and transcription factors were identified from a cell line (C4-2B) of mCRPC by the CUT&Tag assay. Differentially expressed genes (DEGs) between mCRPC and primary prostate cancer (PCa) samples in the GSE35988 dataset were identified. What's more, a recurrence risk prediction model was constructed based on the overlapping genes (termed SE-associated DEGs). To confirm the key SE-associated DEGs, BET inhibitor JQ1 was applied to cells to block SE-mediated transcription. Finally, single-cell analysis was performed to visualize cell subpopulations expressing the key SE-associated DEGs.
Nine human TFs, 867 SE-associated genes and 5417 DEGs were identified. 142 overlapping SE-associated DEGs showed excellent performance in recurrence prediction. Time-dependent receiver operating characteristic (ROC) curve analysis showed strong predictive power at 1 year (0.80), 3 years (0.85), and 5 years (0.88). The efficacy of his performance has also been validated in external datasets. In addition, FKBP5 activity was significantly inhibited by JQ1.
We present a landscape of SE and their associated genes in mCPRC, and discuss the potential clinical implications of these findings in terms of their translation to the clinic.
Solute Carrier Family 6 Member 1 (SLC6A1) has been identified as a cancer-promoting gene in various human cancers, such as clear cell renal cell carcinoma and ovarian cancer. However, its roles in ...prostate cancer (PCa) has not been fully elucidated. The aim of this study was to investigate the expression and clinical significance of SLC6A1 in PCa tissues and its effect on drug resistance to docetaxel in PCa.
Expression patterns of SLC6A1 protein in PCa tissues were examined by immunohistochemistry based on Tissue microarray. Associations of SLC6A1 protein expression with various clinicopathological features and patients' prognosis of PCa were also statistically evaluated based on TCGA data. Roles of SLC6A1 deregulation in prostate carcinogenesis and drug resistance was further determined in vitro and in vivo experiments.
Based on TCGA Dataset, SLC6A1 expression was markedly higher in patients with high Gleason score, advanced clinical stage and positive biochemical recurrence than those with control features (all P < 0.05). Both unvariate and multivariate analyses demonstrated that SLC6A1 expression was significantly associated with biochemical recurrence-free survival in PCa patients. In addition, enforced expression of SLC6A1 effectively promoted cell proliferation, migration and invasion of PCa cells in vitro. Moreover, the inhibition of SLC6A1 suppressed the tumor growth in vivo. Additionally, immunohistochemical notches of PCNA and MMP-9 in the low-expression cluster were pointedly lower compared to those of NC group. Finally, the cell viability revealed that the overexpression of SLC6A1 obviously promoted the PCa cell resistant to docetaxel (DTX), and the transplanted tumor in the overexpression group had no significant reduction compared with the untreated group.
Our data suggest that SLC6A1 overexpression may be associated with aggressive progression and short biochemical recurrence-free survival of PCa, and may be related to the resistance to docetaxel therapy.
Background
To identify biomarkers for guiding therapy and predicting clinical response of Tripterysium Glycosides Tablets (TGT) treatment is an urgent task due to individual differences in TGT ...response across rheumatoid arthritis (RA) patients. Competing endogenous RNA (ceRNA) regulatory system may influence drug response with involvement in diverse biological processes. Herein, we aimed to identify a TGT response‐related ceRNA axis.
Methods
A TGT response‐related ceRNA axis was screened according to clinical cohort‐based RNA expression profiling, lncRNA‐mRNA coexpression, and ceRNA network analyses. Its clinical relevance was evaluated by computational modeling. Regulatory mechanisms of ceRNA axis were also experimentally investigated.
Results
The ceRNA regulatory axis combined with lncRNA ENST00000494760, miR‐654‐5p, and C1QC was identified as a candidate biomarker for RA patients' response to TGT. Both ENST00000494760 and C1QC mRNA expression were significantly lower, while miR‐654‐5p expression was dramatically higher in TGT responders than nonresponders. Its clinical relevance was verified by computational modeling based on both independent clinical validation cohort and collagen‐induced arthritis (CIA) mice. Mechanistically, miR‐654‐5p directly bound to the 3′‐untranslated region of both ENST00000494760 and C1QC mRNA to inhibit their expression. Moreover, miR‐654‐5p suppressed C1QC mRNA expression, but ENST00000494760 bound to miR‐654‐5p and relieved its repression on C1QC mRNA, leading to RA aggressive progression and weak TGT response.
Conclusions
LncRNA ENST00000494760 overexpression may sponge miR‐654‐5p to promote C1QC expression in RA patients. This novel ceRNA axis may serve as a biomarker for screening the responsive RA patients to TGT treatment, which will allow improved personalized healthcare.
Molecular mechanism underlying individual differences in response to Tripterysium Glycosides Tablets (TGT) is inadequate and the solution is limited. A ceRNA regulatory axis with lncRNA ENST00000494760, miR‐654‐5p and C1QC was identified as a candidate biomarker for rheumatoid arthritis (RA) patients' response to TGT. ENST00000494760 may sponge miR‐654‐5p to promote C1QC expression, leading to RA aggressive progression and weak TGT response.
Diagnosis of the presence of tumors and subsequent prognosis based on tumor microenvironment becomes more clinically practical because tumor-adjacent tissues are easy to collect and they are more ...genetically homogeneous. The purpose of this study was to identify new prognostic markers in prostate stroma that are near the tumor. We have demonstrated the prognostic features of FGFR1, FRS2, S6K1, LDHB, MYPT1, and P-LDHA in prostate tumors using tissue microarrays (TMAs) which consist of 241 patient samples from Massachusetts General Hospital (MGH). In this study, we investigated these six markers in the tumor microenvironment using an Aperio Imagescope system in the same TMAs. The joint prognostic power of markers was further evaluated and classified using a new algorithm named Weighted Dichotomizing. The classifier was verified via rigorous 10-fold cross validation. Statistical analysis of the protein expression indicated that in tumor-adjacent stroma FGFR1 and MYPT1 were significantly correlated with patient outcomes and LDHB showed the outcome-association tendency. More interestingly, these correlations were completely opposite regarding tumor tissue as previously reported. The results suggest that prognostic testing should utilize either tumor-enriched tissue or stroma with distinct signature profiles rather than using mixture of both tissue types. The new classifier based on stroma tissue has potential value in the clinical management of prostate cancer patients.
B-cell lymphoma 9 (BCL9) as a co-activator for β-catenin-mediated transcription is highly expressed in tumors. The aim of our study is to investigate the expression of BCL9, and its ...clinicopathological significance in prostate cancer (PCa).
Immunohistochemistry was conducted to analyze the expression of BCL9 in 98 PCa samples and 20 benign prostate hyperplasia (BPH) samples. The associations of BCL9 expression with clinicopathological features and prognosis in PCa patients were analyzed with various statistical methods, such as chi-square test, Kaplan-Meier method and log-rank test.
The positive rate of BCL9 was 53.1% (52/98) in prostate cancer group, and 25.0% (5/20) in benign group (P=0.022). In addition, BCL9 expression in PCa tissues was significantly associated with Gleason score (P=0.016), and biochemical recurrence (P=0.020). Moreover, Kaplan-Meier survival analysis showed that the higher expression of BCL9 was correlated with shorter biochemical recurrence-free survival (P=0.037). However, BCL9 was no
Sorafenib is the most widely used first-line drug for the treatment of the advanced hepatocellular carcinoma (HCC). Unfortunately, sorafenib resistance often limits its therapeutic efficacy. To ...evaluate the efficacy of artesunate against sorafenib-resistant HCC and to investigate its underlying pharmacological mechanisms, a "sorafenib resistance related gene-ART candidate target" interaction network was constructed, and a signaling axis consisting with artesunate candidate target AFAP1L2 and sorafenib target SRC, and the downstream FUNDC1-dependent mitophagy was identified as a major contributor to the sorafenib resistance and a potential way of artesunate to mitigate resistance. Notably, our clinical data demonstrated that AFAP1L2 expression in HCC tissues was markedly higher than that in adjacent non-cancerous liver tissues (P < 0.05), and high AFAP1L2 expression was also significantly associated with an unfavorable overall survival of HCC patients (P < 0.05). Experimentally, AFAP1L2 was overexpressed in sorafenib resistant cells, leading to the activation of downstream SRC-FUNDC1 signaling axis, further blocking the FUNDC1 recruitment of LC3B to mitochondria and inhibiting the activation of mitophagy, based on both in vitro and in vivo systems. Moreover, artesunate significantly enhanced the inhibitory effects of sorafenib on resistant cells and tumors by inducing excessive mitophagy. Mechanically, artesunate reduced the expression of AFAP1L2 protein, suppressed the phosphorylation levels of SRC and FUNDC1 proteins, promoted the FUNDC1 recruitment of massive LC3B to mitochondria, and further overactivated the mitophagy and subsequent cell apoptosis of sorafenib resistant cells. In conclusion, artesunate may be a promising strategy to mitigate sorafenib resistance in HCC via exacerbating AFAP1L2-SRC-FUNDC1 axis-dependent mitophagy.
Abbreviations: AFAP1L2, actin filament associated protein 1 like 2; ANOVA, analysis of variance; ANXA5, annexin V; ART: artesunate; CETSA, cellular thermal shift assay; CI: combination index; CO-IP: co-immunoprecipitation; CQ: chloroquine; CT, computed tomography;
18
F-FDG, fluoro-2-D-deoxyglucose F18; FUNDC1: FUN14 domain containing 1; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HCC, hepatocellular carcinoma; H&E Staining: hematoxylin - eosin staining; HepG2
R
, sorafenib resistant HepG2; IF, immunofluorescence; IHC, immunohistochemistry; LAMP1: lysosomal associated membrane protein 1; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; miR, microRNA; mRNA: messenger RNA; OE, overexpression; OS, overall survival; PET, positron emission tomography; qRT-PCR: quantitative real-time PCR; sh, short hairpin; shNC: negative control shRNA; shAFAP1L2: short hairpin AFAP1L2; SORA, sorafenib; SPR, surface plasmon resonance; SRC, SRC proto-oncogene, non-receptor tyrosine kinase; SUV, standardized uptake value; TEM, transmission electron microscopy; TOMM20: translocase of outer mitochondrial membrane 20.
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