Pancreatic cancer is a highly lethal disease with a poor prognosis, and existing therapies offer only limited effectiveness. Mutation gene sequencing has shown several gene associations that may account for its carcinogenesis, revealing a promising research direction. Poly (ADP-ribose) polymerase (PARP) inhibitors target tumor cells with a homologous recombination repair (HRR) deficiency based on the concept of synthetic lethality. The most prominent target gene is BRCA, in which mutations were first identified in breast cancer and ovarian cancer. PARP inhibitors can trap the PARP-1 protein at a single-stranded break/DNA lesion and disrupt its catalytic cycle, ultimately leading to replication fork progression and consequent double-strand breaks. For tumor cells with BRCA mutations, HRR loss would result in cell death. Pancreatic cancer has also been reported to have a strong relationship with BRCA gene mutations, which indicates that pancreatic cancer patients may benefit from PARP inhibitors. Several clinical trials are being conducted and have begun to yield results. For example, the POLO (Pancreatic Cancer Olaparib Ongoing) trial has demonstrated that the median progression-free survival was observably longer in the olaparib group than in the placebo group. However, PARP inhibitor resistance has partially precluded their use in clinical applications, and the major mechanism underlying this resistance is the restoration of HRR. Therefore, determining how to use PARP inhibitors in more clinical applications and how to avoid adverse effects, as well as prognosis and treatment response biomarkers, require additional research. This review elaborates on future prospects for the application of PARP inhibitors in pancreatic cancer.

The usage of mobile phone increases globally. However, there is still a paucity of data about the impact of electromagnetic fields (EMF) on human health. This study investigated whether EMF radiation would alter the biology of glial cells and act as a tumor-promoting agent. We exposed rat astrocytes and C6 glioma cells to 1950-MHz TD-SCDMA for 12, 24 and 48 h respectively, and found that EMF exposure had differential effects on rat astroctyes and C6 glioma cells. A 48 h of exposure damaged the mitochondria and induced significant apoptosis of astrocytes. Moreover, caspase-3, a hallmark of apoptosis, was highlighted in astrocytes after 48 h of EMF exposure, accompanied by a significantly increased expression of bax and reduced level of bcl-2. The tumorigenicity assays demonstrated that astrocytes did not form tumors in both control and exposure groups. In contrast, the unexposed and exposed C6 glioma cells show no significant differences in both biological feature and tumor formation ability. Therefore, our results implied that exposure to the EMF of 1950-MHz TD-SCDMA may not promote the tumor formation, but continuous exposure damaged the mitochondria of astrocytes and induce apoptosis through a caspase-3-dependent pathway with the involvement of bax and bcl-2.

Introduction: Renal cancer is one of the most common cancers in the world, but the effect of therapies on advanced renal cancer has not improved for decades. Ferroptosis is an emerging type of programmed cell death and has been proved to play a vital role in many kinds of cancers. However, the mechanisms of ferroptosis regulated by long noncoding RNA (lncRNA) in the context of renal cancer was still unknown. Methods: We used bioinformation analysis to identify SLC16A1-AS1 as a survival-related lncRNA in renal cancer. The expression levels of SLC16A1-AS1 and microRNA-143-3p (miR-143-3p) were detected by quantitative reverse transcription–polymerase chain reaction. Cell counting kit-8 assay, 5-bromo-2′-deoxyuridine proliferation assay, and colony-formation assay were performed to evaluate cell viability and proliferation. Wound-healing assay and transwell assay were used to examine cell invasive and migration capacity. Dual-luciferase reporter assay and RNA-binding protein immunoprecipitation were used to identify the interaction among SLC16A1-AS1, miR-143-3p, and the target protein solute carrier family 7 membrane 11 (SLC7A11). Reduced glutathione and glutathione and lipid peroxidation measurements were carried out to evaluate the level of ferroptosis, and the expression levels of ferroptosis-related proteins were analyzed by western blot. Results: Our study revealed that SLC16A1-AS1 has high expression and was associated with overall survival in renal cancer. Knockdown SLC16A1-AS1 inhibited cell viability, proliferation, and migration of renal cancer cells. Furthermore, it was demonstrated that SLC16A1-AS1 served as a sponge of miR-143-3p, and knockdown SLC16A1-AS1 significantly increased the enrichment of miR-143-3p. And then, SLC7A11 was identified as the target protein of miR-143-3p, and overexpression miR-143-3p remarkably inhibited the expression of SLC7A11. Moreover, knockdown SLC16A1-AS1 could aggravate this effect. Finally, through inhibiting SLC7A11 expression, silencing SLC16A1-AS1 induced ferroptosis via increasing miR-143-3p. Conclusion: The present results suggest that silencing lncRNA SLC16A1-AS1 can induce ferroptosis through miR-143-3p/SLC7A11 signaling in renal cancer. Our study provided a novel view into the pathogenesis and treatment strategy of RCC.

CpG methylation in cis-regulatory elements is generally believed to repress gene expression by disrupting transcription factor (TF)-DNA interactions directly or indirectly via the recruitment of proteins containing methyl-CpG-binding domain (MBD), which are largely sequence independent. However, this dogma is challenged by several recent studies including a recent publication by us. In this study, many TFs, including krüppel-like factor 4 (KLF4), were found to preferentially bind to mCpG-containing motifs and transactivate gene expression. Using a site-specific KLF4 mutant (R458A) that abolishes its binding activity to mCpG, but has no impact on binding to its canonical unmethylated motif, we investigated biological function of mCpG-dependent gene regulation by KLF4 in glioblastoma cells. Our studies showed that KLF4 promotes cell adhesion, migration, and morphological changes, all of which are abolished by R458A mutation. We identified over a 100 genes were directly activated via mCpG-dependent KLF4 binding activity. These targets were associated with multiple pathways including pathways involved in cytoskeletal organization, cell adhesion, cytoskeleton, and extracellular matrix. Genes such as NGEF, UGDH, PHLDB2, LIMS2, LM07 and Rabex-5/RABGEF1involved in migration and cytoskeletal organization were highly induced. We validated these targets by Bisulfite Sequencing, ChIP-PCR, RT-PCR and western blot to confirm that they are indeed KLF4-mCpG direct targets. To understand the biological implication of KLF4-mCpG activity and broaden the current understanding of the role of DNA methylation in transcriptional regulation, we utilized one of the direct KLF4-mCpG targets UGDH to investigate this novel epigenetic regulation. UGDH (UDP-α-D-glucose 6-dehydrogenase) is involved in the biosynthesis of the glycosaminoglycan precursor UDP-α-D-glucuronic. Glycosaminoglycans (GAGs) are one of the major components of the cellular environment. Certain GAGs such as Hyaluronic acid (HA) participate in numerous cellular phenomena, including adhesion, motility, angiogenesis and wound healing. UGDH, although upregulated in GBMs has not been implicated in GBM tumor biology. We show that UGDH is required for KLF4-mCpG dependent increase in migration and UGDH knockdown decreases GBM cell proliferation, migration and the abundance of GAGs. Elevated glycosaminoglycan formation is implicated in a variety of human diseases, including the progression of tumors. The inhibition of synthesis of UDP-α-D-glucuronic acid using UGDH antagonists might therefore be a useful strategy for therapy. Note: This abstract was not presented at the meeting. Citation Format: Olutobi Oyinlade, Jun Wan, Shuang Wei, Jiang Qian, Heng Zhu, Shuli Xia. UGDH is required for KLF4-mCpG dependent increase in GBM cell migration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5884. doi:10.1158/1538-7445.AM2017-5884