SETD8 inhibits ferroptosis in pancreatic cancer by inhibiting the expression of RRAD.

BACKGROUND: As an oncogene, SETD8 can promote tumour growth and tumour cell proliferation. This study aims to reveal the relationship between SETD8 and ferroptosis in pancreatic cancer and its role in pancreatic cancer to provide a possible new direction for the comprehensive treatment of pancreatic cancer. METHODS: The downstream targets were screened by RNA sequencing analysis. Western blot, Real-time Quantitative PCR (qPCR) and immunohistochemistry showed the relationship between genes. Cell proliferation analysis and cell metabolite analysis revealed the function of genes. Chromatin immunoprecipitation (CHIP) assays were used to study the molecular mechanism. RESULTS: The potential downstream target of SETD8, RRAD, was screened by RNA sequencing analysis. A negative correlation between SETD8 and RRAD was found by protein imprinting, Real-time Quantitative PCR (qPCR) and immunohistochemistry. Through cell proliferation analysis and cell metabolite analysis, it was found that RRAD can not only inhibit the proliferation of cancer cells but also improve the level of lipid peroxidation of cancer cells. At the same time, chromatin immunoprecipitation analysis (CHIP) was used to explore the molecular mechanism by which SETD8 regulates RRAD expression. SETD8 inhibited RRAD expression. CONCLUSIONS: SETD8 interacts with the promoter region of RRAD, which epigenetically silences the expression of RRAD to reduce the level of lipid peroxidation in pancreatic cancer cells, thereby inhibiting ferroptosis in pancreatic cancer cells and resulting in poor prognosis of pancreatic cancer.

A positive feedback loop of ARF6 activates ERK1/2 signaling pathway via DUSP6 silencing to promote pancreatic cancer progression.

ERK1/2 are essential proteins mediating mitogen-activated protein kinase signaling downstream of RAS in pancreatic adenocarcinoma (PDAC). Our previous study reveals that ARF6 plays a positive regulatory role in ERK1/2 pathway in a feedback loop manner. A significant part of the literature on ARF6 has emphasized its oncogenic effect as an essential downstream molecule of ERK1/2, and no research has been done on the regulation mechanisms of the feedback loop between ARF6 and the ERK1/2 signaling pathway. In the present study, we explore the gene network downstream of ARF6 and find that DUSP6 may be the critical signal molecule in the positive feedback loop between ARF6 and ERK1/2. Specifically, to elucidate the negative correlations between ARF6 and DUSP6 in pancreatic cancer, we examine their expressions in pancreatic cancer tissues by immunohistochemical staining. Then the impact of DUSP6 on the proliferation and apoptosis of PDAC cells are investigated by gain-of-function and loss-of-function approaches. Mechanism explorations uncover that ARF6 suppresses the expression of DUSP6, which is responsible for the dephosphorylation of ERK1/2. Altogether, these results indicate that DUSP6 plays a tumor-suppressive role and acts as an intermediate molecule between ARF6 and ERK1/2 in PDAC cells, thereby forming a positive feedback loop.

The potential of ferroptosis combined with radiotherapy in cancer treatment.

Ferroptosis is a new form of regulatory cell death that is closely related to the balance of redox reactions and the occurrence and development of cancer. There is increasing evidence that inducing ferroptosis in cells has great potential in the treatment of cancer. Especially when combined with traditional therapy, it can improve the sensitivity of cancer cells to traditional therapy and overcome the drug resistance of cancer cells. This paper reviews the signaling pathways regulating ferroptosis and the great potential of ferroptosis and radiotherapy (RT) in cancer treatment and emphasizes the unique therapeutic effects of ferroptosis combined with RT on cancer cells, such as synergy, sensitization and reversal of drug resistance, providing a new direction for cancer treatment. Finally, the challenges and research directions for this joint strategy are discussed.

Influence of Body Mass Index on Perioperative Outcomes Following Pancreaticoduodenectomy.

Background: Overweight and obesity are increasing year by year all over the world, and there is a correlation between overweight and obesity and the risk of pancreatic cancer. However, the relationship between overweight and obesity and perioperative outcomes of pancreaticoduodenectomy (PD) was controversial. The purpose of this study was to investigate the effect of body mass index (BMI) on the perioperative outcome of PD. Methods: This study retrospectively evaluated 227 patients who underwent PD from 2015 to 2019. The patients were divided into three groups: underweight group (BMI <18.5 kg/m2), normal weight group (18.5 ≤ BMI <25 kg kg/m2), and overweight group (BMII ≥25 kg/m2). The association between different BMI groups and different perioperative results was discussed. Finally, the independent risk factors of clinically relevant-postoperative pancreatic fistula (CR-POPF) were analyzed by multivariate logistic regression. Results: The level of preoperative albumin was higher in patients of overweight group (P = .03). The incidence of hypertension increased gradually in the three BMI groups (P = . 039). The preoperative median CA19-9 level was significantly higher in the underweight group than that in the control groups (P = .001). The median operation time in the high BMI group was significantly longer than that in the other two groups. High BMI was an independent risk factor influencing CR-POPF after PD (P = .022, odds ratio 2.253, 95% confidence interval 1.123-4.518). Conclusions: Operation time of PD was increased in patients with high BMI. High BMI was an independent risk factor for the incidence of CR-POPF after PD. However, PD surgery is safe and feasible for patients with different BMI, and overweight and obese patients should not refuse PD surgery because of their BMI.