Background: In this study, we investigated the influences of circBACH1 on the proliferation, metastasis, migration, and apoptosis of human colorectal cancer LoVo cells and explored the molecular mechanism of its effect to guide the clinical diagnosis, treatment, and follow-up of colorectal cancer. Methods: The expression of circBACH1 in colorectal cancer cells was measured to determine the high expression of BACH1 in colorectal cancer (CRC). LoVo was selected for a follow-up experiment. Then, quantificational reverse transcription-polymerase chain reaction (qRT-PCR) and biotinylated let-7a-5p probes were used to confirm that the expression of let-7a-5p was lowered in colorectal cancer, and let-7a-5p was the downstream target of BACH1 in CRC. Cell counting Kit-8 (CCK-8), Transwell, and wound repair experiments confirmed that BACH1 augmented the proliferation, migration, and metastasis of CRC by regulating let-7a-5p. The apoptosis rate was measured by flow cytometry. It was concluded that BACH1 inhibited apoptosis by regulating let-7a-5p in CRC. The results of the bioinformatics analysis showed that CREB5 was overexpressed in CRC by qRT-PCR and Western blot. The results of qRT-PCR, CCK-8 assay, Transwell assay, and flow cytometry showed that let-7a-5p inhibited the proliferation, migration, and invasion of CRC cells through targeting CREB5 and augmented cell apoptosis. According to tumor growth and the determination of CREB5 by Western blot, BACH1 can affect the proliferation of CRC cells through CREB5.Results: Overall, our study confirmed that BACH1 and CREB5 increased, while the expression of let-7a-5p was lowered in colorectal cancer cells. These different expressions enhance the proliferation, metastasis, and migration of colorectal cancer cells and inhibit colorectal cancer cells' apoptosis. Conclusions: Our study clearly illustrates the molecular mechanism of circBACH1 acting on colorectal cancer, which can be used as a therapeutic target to augment colorectal cancer treatment.
Rationale: Targeting vascular smooth muscle cell (VSMC) phenotypic switching is a promising therapeutic approach for atherosclerosis (AS). Dysregulation of PGC1α, a key regulator of cellular energy metabolism, has been implicated in the pathogenesis of AS, yet its role in AS remains controversial. Objective: The current study aimed to determine whether and how PGC1α in VSMCs regulates AS progression. Methods and Results: We generated transgenic (Tg) rabbits with SMC-specific PGC1α overexpression and showed that these rabbits developed significantly less aortic AS than their non-Tg littermates after high-cholesterol diet (HCD) feeding, while total plasma cholesterol levels were similar. As indicated by the restored expression of VSMC differentiation marker genes, the HCD-induced phenotypic switching in the aortic media was largely reversed in Tg rabbits, accompanied by decreased levels of synthetic phenotype genes, proinflammatory cytokines, adhesion molecules, macrophage infiltration, matrix metalloproteinases (MMPs), reactive oxygen species (ROS) production and senescence. Ex vivo studies further showed that VSMC-specific PGC1α overexpression markedly suppressed the promotive effect of HCD feeding on the association of serum response factor (SRF) with ELK1, a ternary complex factor (TCF) that acts as a myogenic repressor in VSMCs, thereby preserving the VSMC contractile phenotype. Furthermore, knockdown of PGC1α remarkably increased extracellular signal-regulated kinase (ERK)1/2-ELK-1 signaling, which promoted phenotypic switching and proliferation of cultured rabbit VSMCs. In addition, we showed that PGC1α can regulate EGFR-ERK1/2 MAP kinase signaling via modulating PPARγ activity in RVSMCs. Finally, we showed that these beneficial results of SMC-specific PGC1α overexpression can be extrapolated from rabbits to human VSMCs and clinical settings. Conclusions: We demonstrated a critical role of PGC1α in maintaining the contractile phenotype of VSMCs and highlighted the therapeutic potential of PGC1α for AS.
BackgroundPredicting the long-term prognosis of individuals who experienced sorafenib treatment following partial hepatectomy due to hepatitis B virus (HBV) related hepatocellular carcinoma (HCC) is difficult. This work aims to create an effective prognostic nomogram for HBV related HCC patients who are receiving sorafenib treatment as adjuvant therapy after surgery.MethodsA total of 233 HBV-related HCC patients treated with or without sorafenib following partial hepatectomy at the Eastern Hepatobiliary Surgery Hospital from 2008 to 2013 were matched with propensity score matching analysis. The optimal cut-off point of the overall survival (OS) factor level was determined by x-tile. The selection of indicators was based on clinical findings. The Cox regression model with an interaction term was employed for evaluating the predictive value. Using a multivariate Cox proportional hazards model, a nomogram was subsequently formulated to analyze 111 patients treated with sorafenib. The nomogram’s discriminative ability and predictive accuracy were determined using the concordance index (C-index), calibration, and ROC curve.ResultsThe matched sorafenib cohort of 111 patients and control cohort of 118 patients were analyzed. Subgroup analysis revealed that low GPC3, pERK, pAKT, serum AFP levels, without MVI, under 50 years old, male, TNM stage I/II and BCLC stage 0/A were significantly associated with a better OS in patients subjected to sorafenib treatment compared to those without sorafenib treatment after surgery. Multivariate analysis of the sorafenib cohort revealed GPC3, pERK, pAKT, serum AST, and BCLC stage as independent factors for OS, and all were included in the nomogram. The survival probability based on the calibration curve showed that the prediction of the nomogram was in good agreement with the actual observation. The C-index of the nomogram for predicting survival was 0.73(95% CI, 0.67–0.78). The area under the ROC curve (AUC) for the nomogram to predict the survival for 1, 3, and 5-year was 0.726, 0.816, and 0.823, respectively.ConclusionThis proposed nomogram shows the potential to make a precise prediction regarding the prognosis of HBV-related HCC patients and may help to stratify patients for personalized therapy following partial hepatectomy.
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