Microbiota is just beginning to be recognized as an important player in carcinogenesis and the interplay among microbes is greater than expected. Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease for which mortality closely parallels incidence. Early detection would provide the best opportunity to increase survival rates. Specific well-studied oral, gastrointestinal, and intrapancreatic microbes and some kinds of hepatotropic viruses and bactibilia may have potential etiological roles in pancreatic carcinogenesis, or modulating individual responses to oncotherapy. Concrete mechanisms mainly involve perpetuating inflammation, regulating the immune system-microbe-tumor axis, affecting metabolism, and altering the tumor microenvironment. The revolutionary technology of omics has generated insight into cancer microbiomes. A better understanding of the microbiota in PDAC might lead to the establishment of screening or early-stage diagnosis methods, implementation of cancer bacteriotherapy, adjustment of therapeutic efficacy even alleviating the adverse effects, creating new opportunities and fostering hope for desperate PDAC patients.

Redox homeostasis is a lifelong pursuit of cancer cells. Depending on the context, reactive oxygen species (ROS) exert paradoxical effects on cancers; an appropriate concentration stimulates tumorigenesis and supports the progression of cancer cells, while an excessive concentration leads to cell death. The upregulated antioxidant system in cancer cells limits ROS to a tumor-promoting level. In cancers, redox regulation interacts with tumor initiation, proliferation, metastasis, programmed cell death, autophagy, metabolic reprogramming, the tumor microenvironment, therapies, and therapeutic resistance to facilitate cancer development. This review discusses redox control and the major hallmarks of cancer.

The epigenetic factor protein arginine methyltransferase 5 (PRMT5) has been reported to play vital roles in a wide range of cellular processes, such as gene transcription, genomic organization, differentiation and cell cycle control. However, its role in pancreatic cancer remains unclear. Our study aimed to investigate the roles of PRMT5 in pancreatic cancer prognosis and progression and to explore the underlying molecular mechanism. Real-time PCR, immunohistochemistry and analysis of a dataset from The Cancer Genome Atlas (TCGA) were performed to study the expression of PRMT5 at the mRNA and protein levels in pancreatic cancer. Cell proliferation assays, including cell viability, colony formation ability and subcutaneous mouse model assays, were utilized to confirm the role of PRMT5 in cell proliferation and tumorigenesis. A Seahorse extracellular flux analyzer, a glucose uptake kit, a lactate level measurement kit and the measurement of 18F-FDG (fluorodeoxyglucose) uptake by PET/CT (positron emission tomography/computed tomography) imaging were used to verify the role of PRMT5 in aerobic glycolysis, which sustains cell proliferation. The regulatory effect of PRMT5 on cMyc, a master regulator of oncogenesis and aerobic glycolysis, was explored by quantitative PCR and protein stability measurements. PRMT5 expression was significantly upregulated in pancreatic cancer tissues compared with that in adjacent normal tissues. Clinically, elevated expression of PRMT5 was positively correlated with worse overall survival in pancreatic cancer patients. Silencing PRMT5 expression inhibited the proliferation of pancreatic cancer cells both in vitro and in vivo. Moreover, PRMT5 regulated aerobic glycolysis in vitro in cell lines, in vivo in pancreatic cancer patients and in a xenograft mouse model used to measure 18F-FDG uptake. We found that mechanistically, PRMT5 posttranslationally regulated cMyc stability via F-box/WD repeat-containing protein 7 (FBW7), an E3 ubiquitin ligase that controls cMyc degradation. Moreover, PRMT5 epigenetically regulated the expression of FBW7 in pancreatic cancer cells. The present study demonstrated that PRMT5 epigenetically silenced the expression of the tumor suppressor FBW7, leading to increased cMyc levels and the subsequent enhancement of the proliferation of and aerobic glycolysis in pancreatic cancer cells. The PRMT5/FBW7/cMyc axis could be a potential therapeutic target for the treatment of pancreatic cancer.

The overall five-year survival rate of pancreatic cancer has hardly changed in the past few decades (less than 10%) because of resistance to all known therapies, including chemotherapeutic drugs. In the past few decades, gemcitabine has been at the forefront of treatment for pancreatic ductal adenocarcinoma, but more strategies to combat drug resistance need to be explored. One promising possibility is ferroptosis, a form of a nonapoptotic cell death that depends on intracellular iron and occurs through the accumulation of lipid reactive oxygen species, which are significant in drug resistance. In this article, we reviewed gemcitabine-resistance mechanisms; assessed the relationship among ferroptosis, tumorigenesis and gemcitabine resistance, and explored a new treatment method for pancreatic cancer.

Patients with pancreatic ductal adenocarcinoma have much worse prognoses, and much effort has been directed toward understanding the molecular biological aspects of this disease. Accumulated evidence suggests that constitutive activation of the Wnt/β-catenin signalling contributes to the oncogenesis and progression of pancreatic cancer. Transcription factor 7-like2/transcription factor 4 (TCF7L2/TCF4), a β-catenin transcriptional partner, plays a vital role in the Wnt/β-catenin signalling pathway. In the present study, we investigated the clinicopathological significance of TCF7L2 in pancreatic cancer. Our results demonstrated that patients with higher TCF7L2 expression had worse prognosis. Our in vitro studies demonstrated that TCF7L2 positively regulated aerobic glycolysis by suppressing Egl-9 family hypoxia inducible factor 2 (EGLN2), leading to upregulation of hypoxia inducible factor 1 alpha subunit (HIF-1α). The impact of TCF7L2 on aerobic glycolysis was further confirmed in vivo by assessing ¹⁸FDG uptake in pancreatic cancer patients and in a subcutaneous xenograft mouse model. In summary, we identified novel predictive markers for prognosis and suggest a previously unrecognized role for TCF7L2 in control of aerobic glycolysis in pancreatic cancer.

Objectives: To investigate the roles of the homeodomain‐interacting protein kinase (HIPK) family of proteins in pancreatic cancer prognosis and the possible molecular mechanism.Materials and Methods: The expression of HIPK family genes and their roles in pancreatic cancer prognosis were analysed by using The Cancer Genome Atlas (TCGA). The roles of HIPK2 in pancreatic cancer proliferation and glycolysis were tested by overexpression of HIPK2 in pancreatic cancer cells, followed by cell proliferation assay, glucose uptake analysis and Seahorse extracellular flux analysis. The mechanism of action of HIPK2 in pancreatic cancer proliferation and glycolysis was explored by examining its effect on the ERK/cMyc axis.Results: Decreased HIPK2 expression indicated worse prognosis of pancreatic cancer. Overexpression of HIPK2 in pancreatic cancer cells decreased cell proliferation and attenuated aerobic glycolysis, which sustained proliferation of cancer cells. HIPK2 decreased cMyc protein levels and expression of cMyc‐targeted glycolytic genes. cMyc was a mediator that regulated HIPK2‐induced decrease in aerobic glycolysis. HIPK2 regulated cMyc protein stability via ERK activation, which phosphorylated and controlled cMyc protein stability.Conclusions: HIPK2 suppressed proliferation of pancreatic cancer in part through inhibiting the ERK/cMyc axis and related aerobic glycolysis.