Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal tumors, with poor therapeutic options in the advanced state. The broccoli-derived anti-inflammatory agent sulforaphane was shown to inhibit the progression of pancreatic cancer and other tumor entities. We examined the involvement of pancreatic cancer cell lines were evaluated by microRNA and gene expression arrays, bioinformatics, in silico analysis, qRT-PCR, western blotting, immunohistochemistry, in situ hybridization, self-renewal and differentiation assays, and in vivo xenograft studies. We selected the top nine differentially expressed microRNAs, and miR135b-5p was chosen as the most important candidate for the sulforaphane-induced upregulation of the tumor suppressor gene RASAL2. The expression of miR135b-5p and RASAL2 was almost absent in malignant pancreatic tissues and cell lines , but not in their normal counterparts. Lipofection of miR135b-5p enhanced RASAL2 expression and inhibited ERK1/2 signaling, viability, self-renewal capacity , and tumor growth. These results indicate that miR135b-5p acts as a tumor suppressor via the induction of RASAL2 in PDA.
Pancreatic ductal adenocarcinoma (PDAC) is extremely malignant and the therapeutic options available usually have little impact on survival. Great hope is placed on new therapeutic targets, including long noncoding RNAs (lncRNAs), and on the development of new drugs, based on e.g., broccoli-derived sulforaphane, which meanwhile has shown promise in pilot studies in patients. We examined whether sulforaphane interferes with lncRNA signaling and analyzed five PDAC and two nonmalignant cell lines, patient tissues (n = 30), and online patient data (n = 350). RT-qPCR, Western blotting, MTT, colony formation, transwell and wound healing assays; gene array analysis; bioinformatics; in situ hybridization; immunohistochemistry and xenotransplantation were used. Sulforaphane regulated the expression of all of five examined lncRNAs, but basal expression, biological function and inhibition of H19 were of highest significance. H19 siRNA prevented colony formation, migration, invasion and Smad2 phosphorylation. We identified 103 common sulforaphane- and H19-related target genes and focused to the virus-induced tumor promoter APOBEC3G. APOBEC3G siRNA mimicked the previously observed H19 and sulforaphane effects. In vivo, sulforaphane- or H19 or APOBEC3G siRNAs led to significantly smaller tumor xenografts with reduced expression of Ki67, APOBEC3G and phospho-Smad2. Together, we identified APOBEC3G as H19 target, and both are inhibited by sulforaphane in prevention of PDAC progression.
Pancreatic ductal adenocarcinoma (PDAC) is among the leading causes of cancer mortality, and new therapeutic options are urgently needed. Long noncoding RNA H19 (H19) is known to promote PDAC progression, but the downstream genes of H19 are largely unknown. Five PDAC cell lines, nonmalignant pancreatic cells, TCGA, GEO-derived pancreatic tissues (malignant, n=413; nonmalignant, n=234), a pancreatic tissue array (n=96), and pancreatic tissues from our clinic (malignant, n=20; nonmalignant, n=20) were examined by a gene array, RT-qPCR, Western blotting, MTT, colony formation, wound-healing, siRNA-mediated gene silencing, bioinformatics, xenotransplantation, and immunohistochemistry assays. The cell cycle inhibitor, UHMK1, was identified to have the strongest correlation with H19. UHMK1 expression was enhanced in PDAC, and high UHMK1 expression correlated with tumor stage, and lower overall survival. siRNA-mediated UHMK1 downregulation inhibited progression signaling. siRNA-mediated downregulation of H19 or UHMK1 inhibited tumor proliferation and xenograft growth. Based on the correlation between UHMK1 expression and clinical parameters, we developed a nomogram that reliably predicts patient prognosis and overall survival. Together, we characterized UHMK1 as an H19-induced oncogene and verified it as a novel PDAC prognostic marker for overall survival.
BackgroundNon‐small‐cell lung cancer (NSCLC) is the leading cause of death from cancer in China. Gefitinib is effective for patients with positive epidermal growth factor receptor gene mutation; however, acquired drug resistance counteracts the duration response. Hyperthermia is widely clinically applied in the treatment of solid tumors. This pilot study was designed to evaluate the feasibility of the combination of gefitinib and hyperthermia.MethodsPatients newly diagnosed with advanced NSCLC were screened. Eleven patients who responded to first‐line gefitinib treatment were enrolled in the study. Along with 250 mg gefitinib daily, local radiofrequency hyperthermia was administered twice a week until tumor progression was observed. The serum, heat shock protein (HSP)70, was also frequently detected during the course.ResultsThe most common toxicity included skin rash (81.8%) and abnormal liver function (45.5%) when treated with gefitinib, and fatty scleroma (36.4%) was observed when combined with hyperthermia. Grade 3 side effects (skin rash) occurred in only one patient. Median progression‐free survival was 22 months (95% confidence interval [CI]: 12.95–31.05 months) and median overall survival was 26 months (95% CI: 22.81–29.19 months). Serum HSP70 concentration increased and maintained a significantly high level compared with the baseline before hyperthermia administration.ConclusionsThe novel therapy of gefitinib combined with radiofrequency hyperthermia is safe and effective for advanced NSCLC patients. Whether an improvement in therapeutic efficacy is associated with the elevation of serum HSP70 concentration requires further study.
Broccoli-derived isothiocyanate sulforaphane inhibits inflammation and cancer. Sulforaphane may support healthy aging, but the underlying detailed mechanisms are unclear. We used the C. elegans nematode model to address this question. Wild-type and 4 mutant C. elegans worm strains were fed in the presence or absence of sulforaphane and E. coli food bacteria transfected with RNA interference gene constructs. Kaplan–Meier survival analysis, live imaging of mobility and pharyngeal pumping, fluorescence microscopy, RT–qPCR, and Western blotting were performed. In the wild type, sulforaphane prolonged lifespan and increased mobility and food intake because of sulforaphane-induced upregulation of the sex-determination transcription factor TRA-1, which is the ortholog of the human GLI mediator of sonic hedgehog signaling. In turn, the tra-1 target gene daf-16, which is the ortholog of human FOXO and the major mediator of insulin/IGF-1 and aging signaling, was induced. By contrast, sulforaphane did not prolong lifespan and healthspan when tra-1 or daf-16 was inhibited by RNA interference or when worms with a loss-of-function mutation of the tra-1 or daf-16 genes were used. Conversely, the average lifespan of C. elegans with hyperactive TRA-1 increased by 8.9%, but this longer survival was abolished by RNAi-mediated inhibition of daf-16. Our data suggest the involvement of sulforaphane in regulating healthy aging and prolonging lifespan by inducing the expression and nuclear translocation of TRA-1/GLI and its downstream target DAF-16/FOXO.
IntroductionHepatocellular carcinoma (HCC) ranks fourth as the most common cause of cancer-related death. It is vital to identify the mechanism of progression and predict the prognosis for patients with HCC. Previous studies have found that cancer-associated fibroblasts (CAFs) promote tumor proliferation and immune exclusion. However, the information about CAF-related genes is still elusive.MethodsThe data were obtained from The Cancer Genome Atlas, International Cancer Genome Consortium, and Gene Expression Omnibus databases. On the basis of single-cell transcriptome and ligand–receptor interaction analysis, CAF-related genes were selected. By performing Cox regression and random forest, we filtered 12 CAF-related prognostic genes for the construction of the ANN model based on the CAF activation score (CAS). Then, functional, immune, mutational, and clinical analyses were performed.ResultsWe constructed a novel ANN prognostic model based on 12 CAF-related prognostic genes. Cancer-related pathways were enriched, and higher activated cell crosstalk was identified in high-CAS samples. High immune activity was observed in high-CAS samples. We detected three differentially mutated genes (NBEA, RYR2, and FRAS1) between high- and low-CAS samples. In clinical analyses, we constructed a nomogram to predict the prognosis of patients with HCC. 5-Fluorouracil had higher sensitivity in high-CAS samples than in low-CAS samples. Moreover, some small-molecule drugs and the immune response were predicted.ConclusionWe constructed a novel ANN model based on CAF-related genes. We revealed information about the ANN model through functional, mutational, immune, and clinical analyses.
Silver nanoparticles (AgNPs) have attracted attention in cancer therapy and might support the treatment of pancreatic ductal adenocarcinoma (PDAC). Silver is in clinical use in wound dressings, catheters, stents and implants. However, the side effects of systemic AgNP treatment due to silver accumulation limit its therapeutic application. We evaluated whether the antioxidant and natural agent α-lipoic acid might prevent these side effects. We synthesized AgNPs using an Ionic-Pulser® Pro silver generator and determined the concentration by inductively coupled plasma–optical emission spectrometry. The effect of α-lipoic acid was examined in four PDAC and two nonmalignant cell lines by MTT, FACS analysis, TEM, xenotransplantation and immunohistochemistry. The viability of PDAC cells was nearly totally abolished by AgNP treatment, whereas nonmalignant cells largely resisted. α-Lipoic acid prevented AgNP-induced cytotoxicity in nonmalignant cells but not in PDAC cells, which might be due to the higher sensitivity of malignant cells to silver-induced cytotoxicity. α-Lipoic acid protected mitochondria from AgNP-induced damage and led to precipitation of AgNPs. AgNPs reduced the growth of tumor xenografts, and cotreatment with α-lipoic acid protected chick embryos from AgNP-induced liver damage. Together, α-lipoic acid strongly reduced AgNP-induced side effects without weakening the therapeutic efficacy.
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