DIAPH3 promotes pancreatic cancer progression by activating selenoprotein TrxR1‐mediated antioxidant effects

Abstract

Pancreatic cancer is a highly malignant tumour of the digestive tract which is difficult to diagnose and treat. Approximately 90% of cases arise from ductal adenocarcinoma of the glandular epithelium. The morbidity and mortality of the disease have increased significantly in recent years. Its 5‐year survival rate is <1% and has one of the worst prognoses amongst malignant tumours. Pancreatic cancer has a low rate of early‐stage diagnosis, high surgical mortality and low cure rate. Selenium compounds produced by selenoamino acid metabolism may promote a large amount of oxidative stress and subsequent unfolded reactions and endoplasmic reticulum stress by consuming the NADPH in cells, and eventually lead to apoptosis, necrosis or necrotic cell death. In this study, we first identified DIAPH3 as a highly expressed protein in the tissues of patients with pancreatic cancer, and confirmed that DIAPH3 promoted the proliferation, anchorage‐independent growth and invasion of pancreatic cancer cells using overexpression and interference experiments. Secondly, bioinformatics data mining showed that the potential proteins interacted with DIAPH3 were involved in selenoamino acid metabolism regulation. Selenium may be incorporated into selenoprotein synthesis such as TrxR1 and GPX4, which direct reduction of hydroperoxides or resist ferroptosis, respectively. Our following validation confirmed that DIAPH3 promoted selenium content and interacted with the selenoprotein RPL6, a ribosome protein subunit involved in selenoamino acid metabolism. In addition, we verified that DIAPH3 could down‐regulate cellular ROS level via up‐regulating TrxR1 expression. Finally, nude mice xenograft model experimental results demonstrate DIAPH3 knock down could decrease tumour growth and TrxR1 expression and ROS levels in vivo. Collectively, our observations indicate DIAPH3 could promote pancreatic cancer progression by activating selenoprotein TrxR1‐mediated antioxidant effects.

Molecular Classification of Breast Cancer Utilizing Long Non-Coding RNA (lncRNA) Transcriptomes Identifies Novel Diagnostic lncRNA Panel for Triple-Negative Breast Cancer

“…A further three transcripts in the final thirteen TNBC-specific lncRNAs are antisense transcripts of diaphanous-related formin 3 (DIAPH3). In hepatocellular carcinoma [ 40 ], lung adenocarcinoma [ 41 ], and pancreatic cancer [ 42 ], the oncogenic roles played by DIAPH3 expression have all been described. In pancreatic cancer, DIAPH3 promoted the proliferation, anchorage-independent growth, and invasion of cancer cells by the activation of selenoprotein TrxR1-mediated antioxidant effects [ 42 ].…”

“…In hepatocellular carcinoma [ 40 ], lung adenocarcinoma [ 41 ], and pancreatic cancer [ 42 ], the oncogenic roles played by DIAPH3 expression have all been described. In pancreatic cancer, DIAPH3 promoted the proliferation, anchorage-independent growth, and invasion of cancer cells by the activation of selenoprotein TrxR1-mediated antioxidant effects [ 42 ]. In lung adenocarcinomas, the knockdown of DIAPH3 inhibited tumorigenesis in both nude mice and in de novo mouse models via impaired ERK signaling [ 41 ].…”

Identification of Pathogenesis and Prognoses of Relapse in Myeloma by Bioinformatic Method

“…SKA1:knockdown of SKA1 shows a signi cant reduction in proliferation of bladder cancer cells [41]. DIAPH3:Highly expressed DIAPH3 promoted proliferation, non-anchored growth and invasion of pancreatic cancer cells [42]. Genes above are upregulated in yellow module,revealing that CENPA and other genes may play a key role in cell cycle,which lead to myeloma recurrence and promote tumor proliferation and drug resistance.…”

Current understanding of ferroptosis in the progression and treatment of pancreatic cancer

“…DIAPH3 also promotes the proliferation and invasion of pancreatic cancer cells. Further mechanistic studies have shown that DIPAH3 inhibition promotes the antioxidant effect mediated by TrxR1 and GPX4, the key factors of selenium metabolism, increases the levels of peroxides and ROS, and ultimately inhibits the malignant phenotype of pancreatic cancer [52]. The magnetic field (MF) is considered to have an anti-tumour effect.…”