STAT3 Phosphorylation Mediating DMSO's Function on Fetal Cardiomyocyte Proliferation with Developmental Changes.

Endogenous cardiac regeneration has been focused for decades as a potential therapy for heart diseases with cell loss, and dimethyl sulfoxide (DMSO) has been proposed as a treatment for many diseases. In this study, we aimed to investigate the function of DMSO on fetal cardiomyocyte proliferation. By tracing BrdU+/α actinin+ cells or Ki67+/α actinin+ cells with immunohistochemical staining, we found that DMSO remarkably promoted fetal cardiomyocytes proliferation, and at the late developmental stage (LDS), such effects were more efficient than that at early developmental stage (EDS). Western blot data revealed a significant increase in STAT3 phosphorylation under DMSO treatments at LDS, while not at EDS. Consistently, STAT3 phosphorylation blocker STA21 could greatly reverse DMSO's function at LDS whereas hardly at EDS. Moreover, hearts at the EDS had less total STAT3 protein, but relatively much higher level of phosphorylated STAT3. This suggests that DMSO promote fetal cardiomyocytes proliferation, and STAT3 phosphorylation play a pivotal role in DMSO's function. With maturation, DMSO exerted a better ability to favor cardiomyocyte proliferation depending on STAT3 phosphorylation. Therefore, DMSO could serve as an effective, economic, and safe therapy for heart diseases with cell loss.

Inhibition of PTPRE suppresses tumor progression and improves sorafenib response in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) has a poor prognosis, and the efficacy of current therapeutic strategies is extremely limited in advanced diseases. Our previous study reported that protein tyrosine phosphatase receptor epsilon (PTPRE) is a promoting factor in HCC progression. In this study, our objective was to evaluate the treatment effect of PTPRE inhibitors in different HCC preclinical models. Our results indicated that the PTPRE inhibitory compound 63 (Cpd-63) inhibited tumor cell proliferation, migration, and HCC organoid growth. Mechanism research revealed that Cpd-63 could inhibit the expression of MYC and MYC targets by inhibiting the activation of SRC. Additionally, we found that Cpd-63 could improve the response of sorafenib in HCC cells. In conclusion, we demonstrated that the PTPRE inhibitors represented a potential therapeutic agent for HCC management.

Disrupting CCDC137-mediated LZTS2 and ß-TrCP interaction in the nucleus inhibits hepatocellular carcinoma development via ß-catenin and AKT.

Hepatocellular carcinoma (HCC) is a highly heterogeneous solid tumor, with its biological characteristics intricately linked to the activation of oncogenes. This research specifically explored CCDC137, a molecule within the CCDC family exhibiting the closest association with HCC. Our investigation aimed to unravel the role, underlying mechanisms, and potential therapeutic implications of CCDC137 in the context of HCC. We observed a close correlation between elevated CCDC137 expression and poor prognosis in HCC patients, along with a promotive effect on HCC progression in vitro and in vivo. Mechanistically, we identified LZTS2, a negative regulator of ß-catenin, as the binding protein of CCDC137. CCDC137 facilitated K48-linked poly-ubiquitination of LZTS2 at lysine 467 via recruiting E3 ubiquitin ligase ß-TrCP in the nucleus, triggering AKT phosphorylation and activation of ß-catenin pathway. Moreover, the 1-75 domain of CCDC137 was responsible for the formation of the CCDC137-LZTS2-ß-TrCP complex. Subsequently, designed peptides targeting the 1-75 domain of CCDC137 to disrupt CCDC137-LZTS2 interaction demonstrated efficacy in inhibiting HCC progression. This promising outcome was further supported by HCC organoids and patient-derived xenograft (PDX) models, underscoring the potential clinical utility of the peptides. This study elucidated the mechanism of the CCDC137-LZTS2-ß-TrCP protein complex in HCC and offered clinically significant therapeutic strategies targeting this complex.

Liver organoids: an in vitro 3D model for liver cancer study.

Primary liver cancer (PLC) is the second leading cause of cancer mortality worldwide, and its morbidity unceasingly increases these years. Hepatitis B virus (HBV) infection accounted for approximately 50% of hepatocellular carcinoma (HCC) cases globally in 2015. Due to the lack of an effective model to study HBV-associated liver carcinogenesis, research has made slow progress. Organoid, an in vitro 3D model which maintains self-organization, has recently emerged as a powerful tool to investigate human diseases. In this review, we first summarize the categories and development of liver organoids. Then, we mainly focus on the functions of culture medium components and applications of organoids for HBV infection and HBV-associated liver cancer studies. Finally, we provide insights into a potential patient-derived organoid model from those infected with HBV based on our study, as well as the limitations and future applications of organoids in liver cancer research.

Long non-coding RNA CCDC183-AS1 acts AS a miR-589-5p sponge to promote the progression of hepatocellular carcinoma through regulating SKP1 expression.

BACKGROUND: Hepatocellular carcinoma (HCC) is a common type of malignant human cancer with high morbidity and poor prognosis, causing numerous deaths per year worldwide. Growing evidence has been demonstrated that long non-coding RNAs (lncRNAs) are closely associated with hepatocarcinogenesis and metastasis. However, the roles, functions, and working mechanisms of most lncRNAs in HCC remain poorly defined. METHODS: Real-time quantitative polymerase chain reaction (qRT-PCR) was used to detect the expression level of CCDC183-AS1 in HCC tissues and cell lines. Cell proliferation, migration and invasion ability were evaluated by CCK-8 and transwell assay, respectively. Animal experiments were used to explore the role of CCDC183-AS1 and miR-589-5p in vivo. Bioinformatic analysis, dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were performed to confirm the regulatory relationship between CCDC183-AS1, miR-589-5p and SKP1. RESULTS: Significantly upregulated expression of CCDC183-AS1 was observed in both HCC tissues and cell lines. HCC patients with higher expression of CCDC183-AS1 had a poorer overall survival rate. Functionally, overexpression of CCDC183-AS1 markedly promoted HCC cell proliferation, migration and invasion in vitro and tumor growth and metastasis in vivo, whereas the downregulation of CCDC183-AS1 exerted opposite effects. MiR-589-5p inhibitor counteracted the proliferation, migration and invasion inhibitory effects induced by CCDC183-AS1 silencing. Mechanistically, CCDC183-AS1 acted as a ceRNA through sponging miR-589-5p to offset its inhibitory effect on the target gene SKP1, then promoted the tumorigenesis of HCC. CONCLUSIONS: CCDC183-AS1 functions as an oncogene to promote HCC progression through the CCDC183-AS1/miR-589-5p/SKP1 axis. Our study provided a novel potential therapeutic target for HCC patients.