SDHA/B reduction promotes hepatocellular carcinoma by facilitating the deNEDDylation of cullin1 and stabilizing YAP/TAZ.

BACKGROUND AND AIMS: Succinate dehydrogenase enzyme (SDH) is frequently diminished in samples from patients with hepatocellular carcinoma (HCC), and SDH reduction is associated with elevated succinate level and poor prognosis in patients with HCC. However, the underlying mechanisms of how impaired SDH activity promotes HCC remain unclear. APPROACH AND RESULTS: In this study, we observed remarkable downregulations of SDH subunits A and B (SDHA/B) in chronic liver injury-induced murine HCC models and patient samples. Subsequent RNA sequencing, hematoxylin and eosin staining, and immunohistochemistry analyses of HCC samples revealed that Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) were significantly upregulated in HCC, with their levels inversely correlating with that of SDHA/B. YAP/TAZ stability was greatly enhanced in SDHA/B-depleted HCC cells along with accumulation of succinate. Further mechanistic analyses demonstrated that impaired activity of SDHA/B resulted in succinate accumulation, which facilitated the deNEDDylation of cullin1 and therefore disrupted the E3 ubiquitin ligase SCF ß-TrCP complex, consequently leading to YAP/TAZ stabilization and activation in HCC cells. The accelerated in vitro cell proliferation and in vivo tumor growth caused by SDHA/B reduction or succinate exposure were largely dependent on the aberrant activation of YAP/TAZ. CONCLUSIONS: Our study demonstrated that SDHA/B reduction promotes HCC proliferation by preventing the proteasomal degradation of YAP/TAZ through modulating cullin1 NEDDylation, thus binding SDH-deficient HCC cells to YAP/TAZ pathway and rendering these cells vulnerable to YAP/TAZ inhibition. Our findings warrant further investigation on the therapeutic effects of targeting YAP/TAZ in patients with HCC displaying reduced SDHA/B or elevated succinate levels.

Cancer-associated fibroblasts drive early pancreatic cancer cell invasion via the SOX4/MMP11 signalling axis.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant cancer-associated fibroblasts (CAFs), early perineural invasion (PNI) and microvascular invasion (MVI). However, the differentiation trajectories and underlying molecular mechanisms of CAFs in PDAC early invasion have not been fully elucidated. In this study, we integrated and reanalysed single-cell data from the National Geoscience Data Centre (NGDC) database and confirmed that myofibroblast-like CAFs (myCAFs) mediated epithelial-mesenchymal transformation (EMT) and enhanced the invasion abilities of PDAC cells by secreting regulators of angiogenesis and metastasis. Furthermore, we constructed a differentiation trajectory of CAFs and revealed that reprogramming from iCAFs to myCAFs was associated with poor prognosis. Mechanistically, SOX4 was aberrantly activated in myCAFs, which promoted the secretion of MMP11 and eventually induced early cancer cell invasion. Together, our results provide a comprehensive transcriptomic overview of PDAC patients with early invasion and reveal the intercellular crosstalk between myCAFs and cancer cells, which suggests potential targets for early invasion PDAC therapy.

Mitigating ammonia volatilization in rice cultivation: The impact of partial organic fertilizer substitution.

Optimizing water and nitrogen management to minimize NH3 volatilization from paddy fields has been extensively studied. However, there is limited research on the combined effect of different rates of organic fertilizer substitution (OFS) and irrigation methods in rice cultivation, exploring an effective water and nitrogen combination is beneficial to mitigate NH3 volatilization. To address this gap, we conducted a two-year field experiment to investigate NH3 volatilization under different OFS rates (0%, 25%, and 50%) combined with continuous flooding irrigation (CF) and alternate wet and dry irrigation (AWD). Our findings revealed that NH3 fluxes exhibited similar emission patterns after each fertilization event and significantly decreased with increasing rates of OFS during the basal stage. Compared to no substitution (ON0), the low (ON25) and high (ON50) rates of OFS reduced cumulative NH3 emissions by 18.9% and 16.6%, and lowed NH3 emission factors (EFs) by 26.7% and 23.3%, respectively. Although OFS resulted in a slight reduction in rice yield, yield-scaled NH3 emissions were significantly reduced by 11.9% and 6.5% under the low and high substitution rates, respectively. This reduction was mainly attributed to the slight yield reduction observed at the low substitution rate. Furthermore, when combined with ON0, AWD irrigation had the potential to increase NH3 volatilization. However, this increase was not observed when combined with ON25 and ON50. During each fertilization stage, floodwater + concentration emerged as the prominent environmental factor influencing NH3 volatilization, showing a stronger and more positive correlation compared to other factors such as floodwater pH, soil pH, and NH4+ concentration. Based on our findings, we recommend implementing effective water and nitrogen management strategies to minimize NH3 volatilization in rice cultivation. This involves applying a lower rate of organic fertilizer substitution during the basal stage, maintaining high water levels during fertilization, and implementing mild AWD irrigation during non-fertilization periods.

Discovery of Novel Indazoles as Potent and Selective PI3Kδ Inhibitors with High Efficacy for Treatment of Hepatocellular Carcinoma.

PI3Kδ inhibitors have been developed for treatment of B-cell malignancies and inflammatory and autoimmune diseases. However, their therapeutic role in solid tumors like hepatocellular carcinoma (HCC) is rarely reported. Thus, the development of potent and selective PI3Kδ inhibitors with a new chemotype and therapy is highly desirable. Through the scaffold-hopping strategy, indazole was first described as the core structure of propeller-shaped PI3Kδ inhibitors. A total of 26 indazole derivatives were designed and prepared to identify a novel compound 9x with good isoform selectivity, PK profile, and potency. Compared to Idelalisib and Sorafenib, the pharmacodynamic (PD) studies showed that 9x exhibits superior efficacy in HCC cell lines and xenograft models, and the mechanistic study showed that 9x robustly suppresses the downstream AKT pathway to induce subsequent apoptotic cell death in HCC models. Therefore, this work provides a new structural design of PI3Kδ inhibitors for a novel and efficient therapeutic small molecule toward HCC.

MicroRNA-9 and breast cancer.

Breast cancer is the most common cancer in women worldwide and seriously impairs patients' physical and mental health. Its incidence has been predicted to rise further. Mounting evidence indicates that microRNAs (miRNAs) play key roles in tumorigenesis and development. It is worth noting that miR-9 exerts critical functions in the initiation and progression of breast cancer, and the present research displays opposite roles of miR-9 in breast cancer. This article mainly reviews the roles of miR-9 in breast cancer progression.