MicroRNA in pancreatic cancer Yonemori, Keiichi; Kurahara, Hiroshi; Maemura, Kosei ...
Journal of human genetics,
01/2017, Letnik:
62, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. Patients with PDAC are often asymptomatic, and many have lymph node and distant metastases as well as vessel invasion ...upon diagnosis. Surgery and current chemotherapy have limited efficacy for improving prognosis, which accounts for overall median survival of 8.6 months and a 9.7% 5-year survival rate. MicroRNAs (miRNAs) are attracting increasing attention because of their association with tumour progression. At least 50% of miRNAs that are aberrantly expressed in tumours have important roles as post-transcriptional regulators and exhibit oncogenic or tumour suppressive activities by directly binding to their target messenger RNAs. Various techniques are available to identify miRNAs that are differentially expressed in cancerous vs normal tissues. In this review, we summarise the miRNA profiles of normal pancreatic tissue and cancer tissue of patients with PDACs and characterise the expression of miRNAs associated with tumour progression. Further, we highlight the target genes and signalling pathways of miRNAs that are aberrantly expressed in PDACs. This knowledge may lead to the development of preventive and therapeutic strategies for treating this deadly disease.
Cholangiocarcinoma (CCA) is a highly malignant cancer of the biliary tract with a poor prognosis, which often arises from conditions causing long-term inflammation, injury, and reparative biliary ...epithelial cell proliferation. Several conditions are known to be major risk factors for cancer in the biliary tract or gallbladder, including primary sclerosing cholangitis, liver fluke infection, pancreaticobiliary maljunction, and chemical exposure in proof-printing workers. Abnormalities in various signaling cascades, molecules, and genetic mutations are involved in the pathogenesis of CCA. CCA is characterized by a series of highly recurrent mutations in genes, including KRAS, BRF, TP53, Smad, and p16(INK4a) . Cytokines that are affected by inflammatory environmental conditions, such as interleukin-6 (IL-6), transforming growth factor-β (TGF-β), tumor necrosis factor-α (TNF-α), and platelet-derived growth factor (PDGF), play an important role in cancer pathogenesis. Prominent signaling pathways important in carcinogenesis include TGF-β/Smad, IL-6/STAT-3, PI3K/AKT, Wnt, RAF/MEK/MAPK, and Notch. Additionally, some microRNAs regulate targets in critical pathways of CCA development and progression. This review article provides the understanding of the genetic and epigenetic mechanism(s) of carcinogenesis in CCA, which leads to the development of new therapeutic targets for the prevention and treatment of this devastating cancer.
Background The roles of infiltrating macrophages within the tumor microenvironment are complex because of their functional variety. The aim of this study is to examine the role and prognostic ...significance of tumor-associated macrophages (TAMs) that have an M2 polarized function in pancreatic cancer. Materials and Methods Formalin-fixed, paraffin-embedded blocks were obtained from 76 patients with pancreatic head cancer. All patients underwent macroscopic curative resection. We assessed the number of infiltrating macrophages within the tumor invasive front by not only CD68 but also by CD163 and CD204, which are specific receptors on M2-polarized macrophages. Furthermore, to evaluate lymphangiogenesis, we measured the density of lymphatic vessels in the tumor invasive front by using D2-40. Results High incidence of lymph node metastasis was shown in cases with a high number of CD163- or CD204-positive macrophages. Significantly increased lymphatic vessel density (LVD) was shown in cases with lymph node metastasis compared with cases without lymph node metastasis ( P = 0.0094). Significantly increased LVD ( P = 0.0175) and a poor prognosis ( P = 0.0171) were shown in cases with a high number of macrophages that express CD163 or CD204, however, there was no significant difference according to the number of CD68-positive macrophages. Conclusions M2-polarized TAMs in the invasive front of pancreatic cancer are associated with a poor prognosis due to accelerated lymphatic metastasis, and inhibition of the functional interaction between M2-polarized TAMs and tumor cells may improve the prognosis.
The neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) are representative blood markers of systemic inflammatory responses. However, the clinical significance of the combination of ...these markers is unclear. This study aimed to investigate the NLR and PLR in patients with advanced gastric cancer treated with chemotherapy and assess the clinical utility of a new blood score combining the NLR and PLR (NLR-PLR score) as a predictor of tumor response and prognosis.
We retrospectively analyzed 175 patients with gastric cancer receiving chemotherapy or chemoradiotherapy. These patients were categorized into progressive disease (PD) and non-PD groups according to tumor response. The NLR and PLR before treatment were examined, and the cut-off values were determined. The NLR-PLR score ranged from 0 to 2 as follows: score of 2, high NLR (> 2.461) and high PLR (> 248.4); score of 1, either high NLR or high PLR; score of 0, neither high NLR nor high PLR.
With regard to tumor response, 64 and 111 patients had PD and non-PD, respectively. The NLR-PLR score was significantly higher in patients with PD than in those with non-PD (p = 0.0009). The prognosis was significantly poorer in patients with a higher NLR-PLR score than in those with a lower NLR-PLR score (p < 0.0001). Multivariate analysis demonstrated that the NLR-PLR score was an independent prognostic factor for prediction of overall survival (p = 0.0392).
Low-cost stratification according to the NLR-PLR score might be a promising approach for predicting tumor response and prognosis in patients with advanced gastric cancer.
Our ongoing analyses identifying dysregulated microRNAs (miRNAs) and their controlled target RNAs have shed light on novel oncogenic pathways in pancreatic ductal adenocarcinoma (PDAC). The PDAC ...miRNA signature obtained by RNA sequencing showed that both strands of pre-miR-130b (miR-130b-5p, the passenger strand and miR-130b-3p, the guide strand) were significantly downregulated in cancer tissues. Our functional assays revealed that miR-130b-5p significantly blocked the malignant abilities of PDAC cell lines (PANC-1 and SW1990), e.g., cancer cell proliferation, migration, and invasion. A total of 103 genes were identified as possible oncogenic targets by miR-130b-5p regulation in PDAC cells based on genome-wide gene expression analysis and in silico database search. Among the possible targets, high expression of 9 genes (EPS8, ZWINT, SMC4, LDHA, GJB2, ZCCHC24, TOP2A, ANLN, and ADCY3) predicted a significantly poorer prognosis of PDAC patients (5-year overall survival, p < 0.001). Furthermore, we focused on EPS8 because its expression had the greatest impact on patient prognosis (overall survival, p < 0.0001). Overexpression of EPS8 was detected in PDAC clinical specimens. Knockdown assays with siEPS8 showed that its overexpression enhanced cancer cell proliferation, migration, and invasion. Analysis of downstream RNA networks regulated by EPS8 indicated that MET, HMGA2, FERMT1, RARRES3, PTK2, MAD2L1, and FLI1 were closely involved in PDAC pathogenesis. Genes regulated by antitumor miR-130b-5p were closely involved in PDAC molecular pathogenesis. Our approach, discovery of antitumor miRNAs and their target RNAs, will contribute to exploring the causes of this malignant disease.
Patients with advanced esophageal squamous cell carcinoma (ESCC) is received chemoradiotherapy or chemotherapy for clinical management. However, it is difficult to predict tumor response and ...prognosis using blood markers before starting treatments. The purpose of this study was to investigate the pre‐treatment plasma fibrinogen and neutrophil–lymphocyte ratio (NLR) in patients with advanced ESCC treated with chemoradiotherapy or chemotherapy, and to assess the clinical utility of a combined score using these blood markers, named as the F‐NLR (fibrinogen and NLR) score, as a predictor of tumor response and prognosis. A total of 98 advanced ESCC patients, treated with chemoradiotherapy or chemotherapy, were classified into three groups: F‐NLR score of 2, having both hyperfibrinogenemia (>400 mg/dL) and high NLR (>3.0), score of 1, one of these hematological abnormalities, and score of 0, having neither hyperfibrinogenemia nor high NLR. Fibrinogen and NLR were significantly higher in the progressive disease (PD) group than the non‐PD group (P = 0.0419, and P = 0.0001, respectively). A significantly higher F‐NLR score was found in the PD group than the non‐PD group (P = 0.0140). Overall survival was significantly lower in patients with an F‐NLR score of 2 than in those with an F‐NLR score of 0 or 1 (P < 0.0001). Multivariate analysis showed that the F‐NLR score was one of the independent prognostic factors (P = 0.0081). Our study demonstrates that the F‐NLR score is promising as a predictive marker for therapeutic effects and prognosis in patients with advanced ESCC.
We demonstrated that the combined score for both plasma fibrinogen and neutrophil‐lymphocyte ratio (named as the F‐NLR score) is a promising blood marker for predicting therapeutic effects and prognosis in patients with advanced esophageal squamous cell carcinoma. The F‐NLR score may serve as an economical biomarker for determining the therapeutic plan in patients with advanced esophageal squamous cell carcinoma.
Background
The usefulness of sentinel node navigation surgery (SNNS) for early gastric cancer has been demonstrated in a multicenter prospective study. However, quality of life (QOL) after local ...resection remains unclear. This present study investigated QOL after local resection and distal gastrectomy.
Methods
We examined 69 patients who underwent laparoscopic distal gastrectomy (LADG) (
n
= 44) and laparoscopic local resection (LLR) (
n
= 25) in our hospital between September 2011 and May 2018. We conducted a combination of laparoscopic and endoscopic approaches to neoplasia with non-exposure technique (CLEAN-NET) with SNNS as LLR. All patients had pStage I or II and none had received adjuvant chemotherapy. We evaluated QOL using the postgastrectomy syndrome assessment scale questionnaire (PGSAS-45) 1, 6, and 12 months after surgery.
Results
In PGSAS-45, no significant differences were observed between LLR and LADG at 1 and 6 months after surgery. At 12 months, the LLR group scored better for some of the subscales (SS). In the endoscopic evaluation, the LLR group showed significant improvements in residual gastritis at 6 months (
P
= 0.006) and esophageal reflux and residual gastritis at 12 months (
P
= 0.021 and
P
= 0.017). A significant difference was observed in the prognostic nutritional index, which was assessed using serum samples, between the two groups at 6 months (
P
= 0.028). The body weight ratio was better in the LLR group than in the LADG group at 6 and 12 months (
P
= 0.041 and
P
= 0.007, respectively).
Conclusions
CLEAN-NET with SNNS preserved a better QOL and nutrition status than LADG in patients with early gastric cancer.
Background & Aims Esophageal squamous cell carcinoma (ESCC) is the predominant form of esophageal cancer in Japan. Smoking and drinking alcohol are environmental risk factors for ESCC, whereas single ...nucleotide polymorphisms in ADH1B and ALDH2 , which increase harmful intermediates produced by drinking alcohol, are genetic risk factors. We conducted a large-scale genomic analysis of ESCCs from patients in Japan to determine the mutational landscape of this cancer. Methods We performed whole-exome sequence analysis of tumor and nontumor esophageal tissues collected from 144 patients with ESCC who underwent surgery at 5 hospitals in Japan. We also performed single-nucleotide polymorphism array-based copy number profile and germline genotype analyses of polymorphisms in ADH1B and ALDH2 . Polymorphisms in CYP2A6, which increase harmful effects of smoking, were analyzed. Functions of TET2 mutants were evaluated in KYSE410 and HEK293FT cells. Results A high proportion of mutations in the 144 tumor samples were C to T substitution in CpG dinucleotides (called the CpG signature) and C to G/T substitutions with a flanking 5′ thymine (called the APOBEC signature). Based on mutational signatures, patients were assigned to 3 groups, which associated with environmental (drinking and smoking) and genetic (polymorphisms in ALDH2 and CYP2A6 ) factors. Many tumors contained mutations in genes that regulate the cell cycle ( TP53, CCND1, CDKN2A , FBXW7 ); epigenetic processes ( MLL2, EP300, CREBBP , TET2 ); and the NOTCH ( NOTCH1 , NOTCH3 ), WNT ( FAT1 , YAP1 , AJUBA ) and receptor-tyrosine kinase−phosphoinositide 3-kinase signaling pathways ( PIK3CA , EGFR , ERBB2 ). Mutations in EP300 and TET2 correlated with shorter survival times, and mutations in ZNF750 associated with an increased number of mutations of the APOBEC signature. Expression of mutant forms of TET2 did not increase cellular levels of 5-hydroxymethylcytosine in HEK293FT cells, whereas knockdown of TET2 increased the invasive activity of KYSE410 ESCC cells. Computational analyses associated the mutations in NFE2L2 we identified with transcriptional activation of its target genes. Conclusions We associated environmental and genetic factors with base substitution patterns of somatic mutations and provide a registry of genes and pathways that are disrupted in ESCCs. These findings might be used to design specific treatments for patients with esophageal squamous cancers.
Background
The necessity of surgical treatment of liver metastases of gastric cancer is still controversial.
Patients and methods
We conducted a multicenter retrospective cohort study of ...liver-limited metastasis of gastric cancer treated surgically between 2000 and 2010. In this study, 103 patients were registered, with nine patients excluded from the analysis as they did not meet the eligibility criteria.
Results
Of the 94 patients, 69 underwent surgical resection, 11 underwent surgical resection combined with radiofrequency ablation or microwave coagulation therapy for small or deep tumors, and 14 underwent radiofrequency ablation or microwave coagulation therapy only. Synchronous and metachronous metastases were found in 37 and 57 patients, respectively. The 3- and 5-year overall survival rates of all the patients were 51.4 and 42.3 %, respectively. The 3- and 5-year relapse-free survival rates were 29.2 and 27.7 %, respectively. No significant difference in prognosis was observed between the patients who underwent surgical resection and those who underwent ablation therapy. The patients with hepatic solitary lesions and low-grade lymph node metastases of primary gastric cancer had significantly better overall survival and relapse-free survival.
Conclusions
To our knowledge, this study is the largest series and first multicenter cohort study of liver-limited metastasis of gastric cancer. The study indicated that patients with a single liver metastasis with a grade lower than N2 lymph node metastasis of the primary lesion are the best candidates for liver resection.
RNA-sequencing-based microRNA (miRNA) expression signatures have revealed that miR-148a-5p (the passenger strand of the miR-148a-duplex) is downregulated in various kinds of cancer tissues. Analysis ...of The Cancer Genome Atlas (TCGA) database showed that low expression of miR-148a-5p was predictive of a lower survival rate (p = 0.041) in patients with gastric cancer (GC). Downregulation of miR-148a-5p was confirmed in GC clinical specimens, and its ectopic expression attenuated GC cell proliferation. Our search for miRNA target genes identified a total of 18 oncogenic targets of miR-148a-5p in GC cells. Among these targets, high expression levels of six genes (THBS2, P4HA3, SERPINH1, CDH11, BCAT1, and KCNG3) were closely associated with a poor prognosis (10-year survival rates) in GC patients (p < 0.05) according to TCGA database analyses. Furthermore, we focused on SERPINH1 as a chaperone protein involved in collagen folding in humans. Aberrant expression of SERPINH1 (mRNA and protein levels) was confirmed in GC clinical specimens. Knockdown assays of SERPINH1 using siRNAs resulted in inhibition of the aggressive phenotype of GC cells. Exploring the molecular networks controlled by miRNAs (including miRNA passenger strands) will broaden our understanding of the molecular pathogenesis of GC.
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