Lei You

MLH1 as a Direct Target of MiR-155 and a Potential Predictor of Favorable Prognosis in Pancreatic Cancer

BackgroundThe regulation of Mut L homologue 1 (MLH1) expression by microRNA (miR)-155 and its prognostic significance in pancreatic cancer (PC) remain to be elucidated. This study aimed to address the issues.MethodsMiR-155 mimics and inhibitor were transfected to PC cell lines, Panc-1 and Capan-1. Expression of MLH1 was subsequently evaluated. Then, luciferase activity was detected after miR-155 mimics and pRL-TK plasmids containing wild-type and mutant 3′UTRs of MLH1 mRNA were co-transfected. Finally, immunohistochemical staining for MLH1 was performed in PC samples.ResultsTransfection of miR-155 mimics and inhibitor led to reversely altered protein expressions of miR-155 and MLH1, whereas the corresponding mRNA expressions were similar. A significant decrease in luciferase activity in the cells transfected with the wild-type pRL-TK plasmid was shown in contrast to those transfected with the mutant one. In addition, MLH1 was less expressed in tumor than in para-tumor tissues of PC. Extensive MLH1 expression was significantly associated with favorable differentiation and less lymph node metastasis. MLH1 expression was found to be a prognosticator in univariate analysis, and being of marginally significant impact in multivariate test.ConclusionsMLH1 might serve as a direct target of miR-155 and a potential prognosis predictor in PC.

Plasma miRNAs Effectively Distinguish Patients With Pancreatic Cancer From Controls: A Multicenter Study.

Objectives:To identify plasma microRNA (miRNA) markers of pancreatic cancer (PC). Background:Accurate pretreatment diagnosis of PC remains challenging, whether plasma miRNAs could be used as biomarkers in PC remains unknown. Methods:In this multiphase multicenter study, peripheral blood samples were obtained preoperatively in 3 phases: the discovery phase [7 patients with PC, 6 patients with chronic pancreatitis (CP), and 5 healthy volunteers (N)], the preliminary validation phase (29 patients with PC, 16 patients with CP, and 31u200aN), and the large sample validation phase (156 patients with PC, 65u200aN, 57 patients with CP, 27 patients with pancreatic neuroendocrine tumors, and 58 patients with other pancreatic tumors). The diagnostic values of the miRNAs were assessed and compared with cancer antigen 19-9 (CA19-9). Results:The discovery phase demonstrated that 29 miRNAs were dysregulated in the patients with PC compared with the controls. In the preliminary validation phase, 13 miRNAs were shown to be dysregulated in the patients with PC and were selected for validation in a multicenter trial. MiR-486-5p exhibited diagnostic value in discriminating patients with PC from normal subjects or patients with CP, with area under the curve values of 0.861 and 0.707, respectively. MiR-938 exhibited diagnostic value in differentiating patients with PC from those with CP, pancreatic neuroendocrine tumors, and patients with other pancreatic tumors, with area under the curve values of 0.693, 0.660, and 0.618, respectively. In addition, we demonstrated that the value of miR-486-5p in discriminating patients with PC from normal subjects or patients with CP was comparable with that of CA19-9 (Pu200a=u200a0.602 and Pu200a=u200a0.230). Conclusions:This study identified several plasma miRNAs potentially suitable for distinguishing patients with PC from normal subjects or patients with other pancreatic tumors.

5-Hydroxymethylcytosine signatures in circulating cell-free DNA as diagnostic biomarkers for human cancers

DNA modifications such as 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) are epigenetic marks known to affect global gene expression in mammals. Given their prevalence in the human genome, close correlation with gene expression and high chemical stability, these DNA epigenetic marks could serve as ideal biomarkers for cancer diagnosis. Taking advantage of a highly sensitive and selective chemical labeling technology, we report here the genome-wide profiling of 5hmC in circulating cell-free DNA (cfDNA) and in genomic DNA (gDNA) of paired tumor and adjacent tissues collected from a cohort of 260 patients recently diagnosed with colorectal, gastric, pancreatic, liver or thyroid cancer and normal tissues from 90 healthy individuals. 5hmC was mainly distributed in transcriptionally active regions coincident with open chromatin and permissive histone modifications. Robust cancer-associated 5hmC signatures were identified in cfDNA that were characteristic for specific cancer types. 5hmC-based biomarkers of circulating cfDNA were highly predictive of colorectal and gastric cancers and were superior to conventional biomarkers and comparable to 5hmC biomarkers from tissue biopsies. Thus, this new strategy could lead to the development of effective, minimally invasive methods for diagnosis and prognosis of cancer from the analyses of blood samples.

Filamin A: Insights into its Exact Role in Cancers.

Filamin A (FlnA) is a well-known actin cross-linking protein. It serves as a scaffold for over 90 binding partners and involves in multiple cell functions, of which cell migration and adhesion is especially critical. Recently, its role in the cell has come under scrutiny for FlnA’s involvement in cancer development. Originally revealed as a cancer-promoting protein, FlnA actually plays a dual role in cancers. When localized to the cytoplasm, FlnA has a tumor-promoting effect by interacting with signaling molecules. While once localized to the nucleus, it may act to suppress tumor growth and inhibit metastasis by interacting with transcription factors. Thus drugs that can cause FlnA to transpose from cytoplasm to nucleus could be a promising treatment for cancers. Study to this end is on the way in prostate cancer and the results are encouraging. FlnA has been studied in large categories of cancers, such as prostate cancer, breast cancer, melanoma, lung cancer, etc. However, most studies did not evaluate the differences that arise from the localization of the protein, which was a great pity! What’s more, although FlnA’s is undoubtedly important in cancer invasion and metastasis, both preclinical and clinical researches are very rare in some highly metastatic cancers, such as pancreatic cancer. In this mini-review, we give a comprehensive summary of FlnA’ s expression in cancers. Where available, we also indicate the correlation of FlnA with cancer stages and patient prognosis, and clarify its localization (nucleus/cytoplasm) and its dual role (promote/suppress) in different cancers.

Plasma microRNA panels to diagnose pancreatic cancer: Results from a multicenter study

Biomarkers for the early diagnosis of pancreatic cancer (PC) are urgent needed. Plasma microRNAs (miRNAs) might be used as biomarkers for the diagnosis of cancer. We analyzed 361 plasma samples from 6 surgical centers in China and performed machine learning approach. We gain insight of the association between the aberrant plasma miRNA expression and pancreatic disease. 671 microRNAs were screened in the discovery phase and 33 microRNAs in the training phase and 13 microRNAs in the validation phase. After the discovery phase and training phase, 2 diagnostic panels were constructed comprising 3 microRNAs in panel I (miR-486-5p, miR-126-3p, miR-106b-3p) and 6 microRNAs in panel II (miR-486-5p, miR-126-3p, miR-106b-3p, miR-938, miR-26b-3p, miR-1285). Panel I and panel II had high accuracy for distinguishing pancreatic cancer from chronic pancreatitis (CP) with area under the curve (AUC) values of 0.891 (Standard Error (SE): 0.097) and 0.889 (SE: 0.097) respectively, in the validation phase. Additionally, we demonstrated that the diagnostic value of the panels in discriminating PC from CP were comparable to that of carbohydrate antigen 19–9 (CA 19–9) 0.775 (SE: 0.053) (P = 0.1 for both). This study identified 2 diagnostic panels based on microRNA expression in plasma with the potential to distinguish PC from CP. These patterns might be developed as biomarkers for pancreatic cancer.

Splenic Preservation Versus Splenectomy During Distal Pancreatectomy: A Systematic Review and Meta-analysis

AbstractBackgroundStudies have been published comparing spleen-preserving distal pancreatectomy (SPDP) with distal pancreatectomy with splenectomy (DPS), but the results remain inconsistent.The aim of this study was to compare SPDP with DPS by conducting a systematic review and meta-analysis.MethodsnLiterature searches of the Medline/PubMed, Embase, and Cochrane Library databases were performed to identify relevant studies published before April 30, 2015. Perioperative outcomes of SPDP and DPS were evaluated. The meta-analysis was performed in random- or fixed-effects models, as appropriate. A subanalysis was conducted to compare the two techniques of splenic preservation: splenic vessel preservation (SVP) and Warshaw technique (WT).ResultsEighteen studies and 1156 patients were included in the comparison between SPDP and DPS. A total of 502 of these patients underwent SPDP and 654 underwent DPS. Meta-analysis showed the SPDP group had significantly fewer infectious complications (odds ratio [OR] 0.57, Pxa0=xa00.006), less operative blood loss (Pxa0<xa00.0001), lower overall morbidity rate (OR 0.66, Pxa0=xa00.002), and lower clinical pancreatic fistula rate (OR 0.42, Pxa0=xa00.002) than the DPS group. Subanalysis indicated the SVP group had significantly lower rate of spleen infarction (OR 0.12, Pxa0<xa00.00001) and fewer secondary splenectomies (OR 0.13, Pxa0=xa00.008) than the WT group.ConclusionsSPDP was a safe procedure associated with better short-term outcomes than DPS. SVP could provide more sufficient blood perfusion for the conserved spleen than WT. However, the evidence is limited, and more randomized controlled trials are warranted.

The Effect of Prophylactic Central Neck Dissection on Locoregional Recurrence in Papillary Thyroid Cancer After Total Thyroidectomy: A Systematic Review and Meta-Analysis : pCND for the Locoregional Recurrence of Papillary Thyroid Cancer.

BackgroundThe use of prophylactic central neck dissection (pCND) for papillary thyroid cancer (PTC) without clinical evidence of nodal metastasis (cN0) remains controversial. This study was designed to examine whether pCND for PTC affected locoregional recurrence (LRR).MethodsA systematic review was performed to compare the LRR between patients with PTC who underwent total thyroidectomy (TT) and pCND and those who underwent TT alone. The primary outcome was LRR. Other outcomes, including postoperative radioiodine (RAI) ablation and surgically related complications, were evaluated. A meta-analysis was performed using the random-effects model.ResultsWe included 17 studies, which comprised 4437 patients. Patients in the TT+pCND group had a significantly reduced risk of LRR (risk ratio [RR]xa0=xa00.66; 95% confidence interval [CI]: 0.49–0.90; Pxa0=xa00.008). The LRR in the central neck compartment (RRxa0=xa00.35; 95% CI 0.18–0.68; Pxa0=xa00.002) was significantly lower in the TT+pCND group, whereas the LRR in the lateral neck compartment was similar between the two groups. Compared with the TT alone group, patients in the TT+pCND group tended to receive higher RAI (74.6% vs. 59.9%) and experience temporary hypocalcemia (odds ratio [OR]xa0=xa02.37; 95% CI 1.89–2.96; Pxa0<xa00.00001), permanent hypocalcemia (ORxa0=xa01.93; 95% CI 1.05–3.57; Pxa0=xa00.03), and increased overall morbidity (ORxa0=xa02.56; 95% CI 1.75–3.74; Pxa0<xa00.00001).ConclusionsThis meta-analysis suggested that although pCND reduced the LRR in PTC—specifically in the central neck compartment—it was accompanied by an increased rate of postoperative hypocalcemia. However, the evidence is limited and randomized, controlled trials are needed to clarify this role further.

miR-497 expression, function and clinical application in cancer

MicroRNAs (miRNAs) are small non-coding RNAs that inhibit gene expression by binding to the 3′ untranslated region (3′-UTR) of their target mRNAs. Recent studies show that miR-497 plays an important role in various cancers. Here, we summarize the existing studies of miR-497 as following: (1) miR-497 expression in cancer; (2) regulation mechanisms of miR-497 expression; (3) function of miR-497 in cancer; (4) direct targets of miR-497; (5) Clinical applications of miR-497. Recent analyses verify that miR-497 mainly suppresses tumors; however, it also acts as an oncogene in several cancers. Increasing evidence indicates that miR-497 can serve as a diagnostic and prognostic biomarker and is a promising therapeutic target for future clinical applications.

N-WASP in Pancreatic Ductal Adenocarcinoma: Associations with Perineural Invasion and Poor Prognosis

AbstractBackgroundnPancreatic ductal adenocarcinoma (PDAC) has long been acknowledged to have a dismal prognosis. Therefore, prognostic markers, especially molecular ones, are of interest. So far, expression of Neural Wiskott-Aldrich syndrome protein (N-WASP) and its associations with clinicopathologic variables and prognosis for patients with PDAC remain unknown.MethodsN-WASP expression was detected by immunohistochemical staining in a tissue microarray consisted of tumor and nontumor samples from 86 patients with PDAC. The correlations of N-WASP expression with clinicopathologic features and overall survival were evaluated. In addition, risk factors of perineural invasion (PNI) were identified.ResultsHigh expression of N-WASP was more frequent in tumor than in nontumor tissues of PDAC patients (45.3 vs. 19.8xa0%, pxa0<xa00.001). The rank of N-WASP grading was significantly higher in tumor tissues than in nontumor tissues (pxa0=xa00.048). Also, high expression of N-WASP in tumor tissues was significantly associated with PNI, and lymph node status had a marginally significant relation to tumoral N-WASP expression. Univariate analyses showed that, in addition to conventional clinicopathologic variables, including sex, histologic grade, PNI and lymph node metastasis, high tumoral N-WASP expression was an independent marker of PNI and served as a significant predictor of poor overall survival. The prognostic implication of N-WASP expression was not proven In the multivariate analysis.ConclusionsOur data showed highly up-regulated expression of N-WASP in PDAC tissues, its correlations with PNI, and its association with an unfavorable prognosis.

CXCL12-CXCR7 axis contributes to the invasive phenotype of pancreatic cancer

Chemokine (C-X-C motif) receptor 7 (CXCR7) and its ligand, chemokine (C-X-C motif) ligand 12 (CXCL12), were established to be involved in biological behaviors and associated with prognosis in many cancers. However, effects, underlying mechanisms of CXCL12-CXCR7 axis in invasive phenotype of pancreatic cancer (PC) and its clinicopathologic significances have not been comprehensively explored. In the present study, it was first found by tissue microarray-based immunohistochemistry that CXCL12 and CXCR7 staining scores were significantly associated with vessel invasion and overall survival in two independent cohorts of PC. Besides, co-expression of these proteins was an independent prognosticator in multivariate analysis in both cohorts. Then, migration and invasion, but not proliferation, were decreased in CXCR7-stably silenced PC cells, whereas opposite changes were observed in CXCR7-stably overexpressed cells, accompanied by alterations of mTOR and Rho/ROCK pathways. CXCL12 stimulated migration, invasion, CXCR7 expression and phosphorylation of key mTOR proteins. AMD3100 did not influence effects of CXCL12. Two mTOR inhibitors, rapamycin and Torin1, reversed enhanced invasive phenotypes and mTOR phosphorylation in CXCR7-overexpressed cells. Moreover, CXCR7 directly interacts with mTOR. Finally, liver metastasis, but not growth, was affected by CXCR7 status in orthotopically-implanted PC models in nude mice. Collectively, CXCL12-CXCR7 axis accelerates migration and invasion of PC cells through mTOR and Rho/ROCK pathways, and predicts poor prognosis of PC.