DNA methyltransferase mediates the hypermethylation of the microRNA 34a promoter and enhances the resistance of patient-derived pancreatic cancer cells to molecular targeting agents.

Purpose To determine the safety and efficacy of sorafenib combined with transarterial chemoembolization (TACE) and radiofrequency ablation (RFA) (hereafter, S-TACE-RFA) in patients with medium or large (range, 3.1-7.0 cm in diameter) hepatocellular carcinoma (HCC). Materials and Methods This retrospective study evaluated the medical records of consecutive patients with medium or large HCC who underwent S-TACE-RFA or combined TACE and RFA (hereafter, TACE-RFA) from January 2010 to December 2014. Sorafenib was started 3-5 days after TACE, and RFA was performed 1-2 weeks after TACE. Treatment complications, recurrence-free survival (RFS), and overall survival (OS) in patients who underwent S-TACE-RFA were compared with those in patients who underwent TACE-RFA. Results Of the 174 patients who underwent S-TACE-RFA or TACE-RFA, 106 who met the eligibility criteria were included in this study. Among them, 40 underwent S-TACE-RFA and 66 underwent TACE-RFA. The patients who underwent S-TACE-RFA had longer RFS (median, 24.0 vs 10.0 months; P = .04) and better OS (median, 63.0 vs 36.0 months, P = .048) than those who underwent TACE-RFA. S-TACE-RFA and α-fetoprotein level were independent prognostic factors for survival in uni- and multivariable analyses. The rate of complications in patients who underwent S-TACE-RFA was similar to that in patients who underwent TACE-RFA (22.5% vs 18.2%, P = .59). Conclusion S-TACE-RFA resulted in longer RFS and better OS than did TACE-RFA in patients with medium or large HCC. © RSNA, 2018 Online supplemental material is available for this article.

https://pubs.rsna.org/doi/pdf/10.1148/radiol.2018172028

Medium or Large Hepatocellular Carcinoma: Sorafenib Combined with Transarterial Chemoembolization and Radiofrequency Ablation

Procaspase-3-activating compound 1 (PAC-1) induces procaspase-3 activation via zinc chelation. However, whether PAC-1 employs other mechanisms remains unknown. Here we systematically screened for potent PAC-1 targets using 29 enhanced green fluorescent protein-labeled reporter cell lines and identified hypoxia-inducible factor 1α (HIF1α) and RAD51 pathways as PAC-1 targets. These results were verified in HepG2 cells and two other cancer cell lines. Mechanistically, PAC-1 specifically blocked HIF1α hydroxylation and upregulated HIF1α target genes. In addition, DNA damage, G1/S cell cycle arrest, and the inhibition of DNA synthesis were induced following PAC-1 administration. Interestingly, by using ferrozine-iron sequestration and iron titration assays, we uncovered the iron sequestering capacity of PAC-1. Additionally, the expression levels of iron shortage-related genes were also increased in PAC-1-treated cells, and iron (II) supplementation reversed all of the observed cellular responses. Thus, our results indicate that PAC-1 induces HIF1α stabilization and DNA damage by sequestering ferrous iron.

/pdf/procaspase-3-activating-compound-1-stabilizes-hypoxia-35lc3ja7kz.pdf

Procaspase-3-activating compound 1 stabilizes hypoxia-inducible factor 1α and induces DNA damage by sequestering ferrous iron.

Upregulated long non-coding RNA AGAP2-AS1 represses LATS2 and KLF2 expression through interacting with EZH2 and LSD1 in non-small-cell lung cancer cells.

Bladder cancer is one of the most common malignant tumors worldwide. Accordingly, its incidence and mortality are high. One of the characteristics of cancer is genomic instability. New studies suggest that long non-coding RNAs (lncRNAs) play an important role in maintaining genomic instability. This study aimed to identify a genomic instability-associated lncRNA signature to predict the outcome of patients with bladder cancer. We downloaded data for bladder cancer patients from The Cancer Genome Atlas database to obtain lncRNA expression profiles as well as somatic mutation profiles. Using the lncRNA computational framework, a genomic instability-related lncRNA signature (GIlncSig) was established and the prognostic value of this signature was assessed and validated. A five-lncRNA signature based on genomic instability (CFAP58-DT, MIR100HG, LINC02446, AC078880.3, and LINC01833) was obtained from 58 differentially expressed lncRNAs. Patients were divided into high-risk and low-risk groups, with the high-risk group having a substantially worse prognosis than the low-risk group. Univariate and multivariate Cox analyses indicated that GIlncSig may be an independent prognostic factor; this finding was subsequently validated. In addition, enrichment analysis indicated that GIlncSig is associated with genomic instability in bladder cancer. GIlncSig has a predictive value for the prognosis of bladder cancer patients and provides guidance for the clinical treatment of these patients.

https://www.tandfonline.com/doi/pdf/10.1080/21655979.2021.1924555

Prediction of bladder cancer outcome by identifying and validating a mutation-derived genomic instability-associated long noncoding RNA (lncRNA) signature

Introduction Bladder cancer (BC) is the fourth-commones cancer and the sixth-leading cause of cancer-related death among men. However, a lack of reliable biomarkers remains a problem forprognosis and treatment of BC. lncRNAs have been shown to play important roles in various cancers, and have emerged as promising biomarkers for cancer prognosis and treatment.
 Methods
 In this study, using univariate and multivariate Cox regression analysis, we examined the differential expression profiles of 1,651 lncRNAs in the TCGA BLCA cohort and created a prognostic gene signature composed of six lncRNAs (for SNHG12, MAFG-
 DT, ASMTL-AS1, LINC02321, LINC01322, and LINC00922), designed the SMALLL signature.
 Results
 The SMALLL signature displayed significant prognostic power for overall survival for BC patients in multiple cohorts. Gene Ontology analysis showed that genes coexpressed with the SMALLL signature were associated with the extracellular matrix network, and immune cell–infiltration analysis showed that activated naive B cells, regulatory T cells, M0 macrophages, eosinophils, resting memory CD4 T cells and resting NK cells were significantly different in high- and low-risk groups. We also confirmed differential expression of the lncRNAs of the SMALLL signature in BC tissue and paracancer normal tissue by qRT-PCR analysis. Cell-invasion and -migration experiments showed that MAFG-AS1, ASMTL-AS1, LINC02321, and LINC00922 significantly affected cell invasion and migration.
 Conclusion
 Our study revealed that the lncRNA signature is an important predictive factor of prognosis and provides a promising biomarker for BC.

/pdf/extracellular-matrix-related-six-lncrna-signature-as-a-novel-4p51hnzvzl.pdf

Extracellular Matrix–Related Six-lncRNA Signature as a Novel Prognostic Biomarker for Bladder Cancer

Background Despite progress achieved in bladder cancer (BC) treatment, the prognosis of patients with advanced BC (ie, metastasized from the bladder to other organs) is poor. Although mortality in cases of low-grade BC is rare, the treatment, such as a radical cystectomy, often has a serious impact on the quality of life. Thus, research is needed to identify more effective treatment strategies and this work is aiming to examine the potential application of combination of radiofrequency ablation (RFA) and SB435142, a inhibitor of transforming growth factor β (TGFβ)/Smad pathway. Methods BC cells were transplanted into nude mice (thymusdeficiency Bal B/c) to form subcutaneous tumors. The mice with subcutaneous tumors were then treated with RFA and oral administration of SB431542, an inhibitor of TGFβ/Smad signaling pathway. The antitumor effect of RFA was measured by tumor proliferation curves and micro-positron emission computed tomography (micro-PET). The effect of SB431542 on epithelial-mesenchymal transition (EMT) related regulators in subcutaneous tumor tissues formed by BC cells were examined by quantitative real-time polymerase chain reaction (qPCR) experiments. Results The SB431542 treatment enhanced the antitumor effect of RFA on subcutaneous growth of BCs. SB431542 also decreased EMT-related regulators in subcutaneous tumor tissues formed by BC cells in nude mice. Conclusion SB431542 enhances the effect of RFA on BC.

The TGF-β/Smad Pathway Inhibitor SB431542 Enhances The Antitumor Effect Of Radiofrequency Ablation On Bladder Cancer Cells.

Prostate cancer remains a significant cause of cancer-related deaths in male population. More recently, accumulating evidence continues to implicate long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and mRNAs in various types of cancers, including prostate cancer. The current study aimed to elucidate the role of lncRNA AGAP2-AS1/miR-195-5p/PDZ and LIM domain 5 (PDLIM5) in prostate cancer progression. Initially, microarray expression profiles were applied to screen differentially expressed lncRNAs/miRNAs/genes associated with prostate cancer. Dual-luciferase reporter and RNA pull-down/RIP assays were subsequently performed to explore the interactions among lncRNA AGAP2-AS1, miR-195-5p, and PDLIM5, after which their expression was detected in cancer tissues and cells. Next, gain- and loss-of-function approaches were employed to elucidate the mechanism of lncRNA AGAP2-AS1/miR-195-5p/PDLIM5 in the processes of cell proliferation, migration and invasion as well as tumor growth. LncRNA AGAP2-AS1 was found to be highly expressed in prostate cancer. Silencing of lncRNA AGAP2-AS1 contributed to the suppression of proliferation, migration and invasion of cancer cells in vitro. Besides, lncRNA AGAP2-AS1 could bind to miR-195-5p which targeted PDLIM5 and subsequently downregulated its expression, ultimately impeding the progression of prostate cancer. Additionally, lncRNA AGAP2-AS1 inhibition led to an up-regulated expression of miR-195-5p and down-regulated PDLIM5 expression, resulting in delayed tumor growth in vivo. Taken together, the key findings of our study demonstrated that lncRNA AGAP2-AS1 silencing exerted suppressive effects on the development of prostate cancer via the miR-195-5p-dependent downregulation of PDLIM5. Our findings highlighted the potential of lncRNA AGAP2-AS1 as a promising novel molecular target for prostate cancer therapy.

Long Non-coding RNA AGAP2-AS1 Silencing Inhibits PDLIM5 Expression Impeding Prostate Cancer Progression via Up-Regulation of MicroRNA-195-5p.

The prognosis for endocrine-independent prostate carcinoma is still poor due to its highly metastatic feature. In the present work, TPX2 (the targeting protein for Xklp2), which is known as a micro-tubulin interacted protein, was identified as a novel coactivator of ETS-1, a transcription factor that plays a central role in mediating the metastasis of human malignancies. TPX2 enhanced the transcription factor activation of ETS-1 and increased the expression of ETS-1's downstream metastasis-related genes, such as mmp3 or mmp9, induced by HGF (hepatocyte growth factor), a typical agonist of the HGF/c-MET/ETS-1 pathway. The protein-interaction between TPX2 and ETS-1 was examined using immunoprecipitation (IP). TPX2 enhanced the accumulation of ETS-1 in the nuclear and the recruitment of its binding element (EST binding site, EBS) located in the promoter region of its downstream gene, mmp9. Moreover, TPX2 enhanced the in vitro or in vivo invasion of a typical endocrine-independent prostate carcinoma cell line, PC-3. Therefore, TPX2 enhanced the activation of the HGF/ETS-1 pathway to enhance the invasion of endocrine-independent prostate carcinoma cells and thus it would be a promising target for prostate carcinoma treatment.

/pdf/tpx2-enhanced-the-activation-of-the-hgf-ets-1-pathway-and-3s79p3spa7.pdf

TPX2 Enhanced the Activation of the HGF/ETS-1 Pathway and Increased the Invasion of Endocrine-Independent Prostate Carcinoma Cells

The arachidonic acid (AA) metabolic pathway participates in various physiological processes as well as in the development of malignancies. We analyzed genomic alterations in AA metabolic enzymes in the Cancer Genome Atlas (TCGA) prostate cancer (PCa) dataset and found that the gene encoding soluble epoxide hydrolase (EPHX2) is frequently deleted in PCa. EPHX2 mRNA and protein expression in PCa was examined in multiple datasets by differential gene expression analysis and in a tissue microarray by immunohistochemistry. The expression data were analyzed in conjunction with clinicopathological variables. Both the mRNA and protein expression levels of EPHX2 were significantly decreased in tumors compared with normal prostate tissues and were inversely correlated with the Gleason grade and disease-free survival time. Furthermore, EPHX2 mRNA expression was significantly decreased in metastatic and recurrent PCa compared with localized and primary PCa, respectively. In addition, EPHX2 protein expression correlated negatively with Ki67 expression. In conclusion, EPHX2 deregulation is significantly correlated with the clinical characteristics of PCa progression and may serve as a prognostic marker for PCa.

Mingsheng Liu

Papers

Extracellular Matrix–Related Six-lncRNA Signature as a Novel Prognostic Biomarker for Bladder Cancer

The TGF-β/Smad Pathway Inhibitor SB431542 Enhances The Antitumor Effect Of Radiofrequency Ablation On Bladder Cancer Cells.

Long Non-coding RNA AGAP2-AS1 Silencing Inhibits PDLIM5 Expression Impeding Prostate Cancer Progression via Up-Regulation of MicroRNA-195-5p.

TPX2 Enhanced the Activation of the HGF/ETS-1 Pathway and Increased the Invasion of Endocrine-Independent Prostate Carcinoma Cells

Clinical significance of EPHX2 deregulation in prostate cancer