HGF/c-MET pathway contributes to cisplatin-mediated PD-L1 expression in hepatocellular carcinoma.

Cisplatin has been reported to promote the expression of programmed cell death ligand-1 (PD-L1) in some cancer cells. However, the underlying mechanism through which PD-L1 is transcriptionally regulated by cisplatin in hepatocellular carcinoma (HCC) cells remains largely unknown. In the present study, we found that the expression of hepatocyte growth factor (HGF), p-Akt, p-ERK, and PD-L1 was increased in cisplatin-treated SNU-368 and SNU-739 cells. HGF stimulation also increased PD-L1 expression in these cells. Moreover, Inhibition of HGF/c-MET, PI3K/Akt, and MEK/ERK signaling pathways can dramatically block cisplatin or HGF-induced PD-L1 expression in SNU-368 and SNU-739 cells. In vivo, combination PHA665752 with cisplatin significantly reduced tumor weight with increased infiltration of CD8+ T cells in the tumor. Taken together, our study suggested that HGF/c-Met axis-induced the activation of PI3K/Akt and MEK/ERK pathways contributes to cisplatin-mediated PD-L1 expression. These findings may provide an alternative avenue for the treatment of HCC.

Evidence that growth hormone can improve mitochondrial function in oocytes from aged mice.

Decline in successful conception decreases more rapidly after 38 years of age owing to follicular depletion and decreased oocyte quality. However, limited information is available regarding the underlying mechanism and the useful treatment. This study aimed to evaluate the effects of growth hormone supplementation on oocyte maturation in vivo in aged and young mice and to determine its effect on mitochondrial function. The influence of three different doses of recombinant human growth hormone (rhGH) (0.4, 0.8 and 1.6 mg/kg/day) for 8 weeks before ovarian stimulation was analyzed. Superovulated oocytes were released from the oviduct of 12-week-old and 40-week-old female C57BL/6J mice 14-16 h after administration of human chorionic gonadotropin. Ovarian follicle and morphological analysis and oocyte maturation parameters were then evaluated. This study is the first, to our knowledge, to report that medium- and high-dose rhGH significantly increases antral follicles in aged mice but anti-Müllerian hormone (AMH) levels. Furthermore, derived oocytes, MII-stage oocyte rate, ATP levels, mitochondrial membrane potential and frequencies of homogeneous mitochondrial distribution increased. In contrast, in both aged and young mice, the mtDNA copy numbers per oocyte were similar before rhGH administration, and upon saline administration, they did not differ significantly. We conclude that medium-dose rhGH supplementation before standard ovarian stimulation regimens improves oocyte quality in aged mice, probably by enhancing mitochondrial functionality.

Stress signaling in response to polycyclic aromatic hydrocarbon exposure in Arabidopsis thaliana involves a nucleoside diphosphate kinase, NDPK-3.

MAIN CONCLUSION: The study is the first to reveal the proteomic response in plants to a single PAH stress, and indicates that NDPK3 is a positive regulator in the Arabidopsis response to phenanthrene stress. Polycyclic aromatic hydrocarbons (PAHs) are highly carcinogenic pollutants that are byproducts of carbon-based fuel combustion, and tend to persist in the environment for long periods of time. PAHs elicit complex, damaging responses in plants, and prior research at the physiological, biochemical, and transcriptional levels has indicated that reactive oxygen species (ROS) and oxidative stress play major roles in the PAH response. However, the proteomic response has remained largely unexplored. This study hypothesized that the proteomic response in Arabidopsis thaliana to phenanthrene, a model PAH, would include a strong oxidative stress signature, and would provide leads to potential signaling molecules involved. To explore that proteomic signature, we performed 2D-PAGE experiments and identified 30 proteins levels that were significantly altered including catalases (CAT), ascorbate peroxidase (APX), peroxiredoxins (POD), glutathione-S-transferase, and glutathione reductase. Also upregulated was nucleoside diphosphate kinase 3 (NDPK-3), a protein known to have metabolic and stress signaling functions. To address whether NDPK-3 functions upstream of the oxidative stress response, we measured levels of stress-responsive enzymes in NDPK-3 overexpressor, loss-of-function knockout, and wild-type plant lines. In the NDPK-3 overexpressor, the enzyme activities of APX, CAT, POD, as well as superoxide dismutase were all increased compared to wild type; in the NDPK-3 knockout line, these enzymes had reduced activity. This pattern occurred in untreated as well as phenanthrene-treated plants. These data support a model in which NDPK-3 is a positive regulator of the Arabidopsis stress response to PAHs.