Xueshuai Wan

Long Noncoding RNA Plays a Key Role in Metastasis and Prognosis of Hepatocellular Carcinoma

Long noncoding RNAs (lncRNAs) have been attracting immense research interests. However, only a handful of lncRNAs had been thoroughly characterized. They were involved in fundamental cellular processes including regulation of gene expression at epigenetics as well as tumorogenesis. In this paper, we give a systematic and comprehensive review of existing literature about lncRNA involvement in hepatocellular carcinoma. This review exhibited that lncRNAs played important roles in tumorigenesis and subsequent prognosis and metastasis of hepatocellular carcinoma and elucidated the role of some specific lncRNAs such as MALAT1 and HOTAIR in the pathophysiology of hepatocellular carcinoma and their potential of being therapeutic targets.

Long non-coding RNA expression profiles of hepatitis C virus- related dysplasia and hepatocellular carcinoma

Recently, long non-coding RNAs (lncRNAs) were found to be implicated in cancer progression. However, the contributions of lncRNAs to Hepatitis C virus-related hepatocellular carcinoma (HCC) remain largely unknown. Here, we characterized lncRNA expression in 73 tissue samples from several different developmental stages of HCV-related hepatocarcinogenesis by repurposing microarray data sets. We found that the expression of 7 lncRNAs in preneoplastic lesions and HCC was significantly different. Among these significantly differently expressed lncRNAs, the lncRNA LINC01419 transcripts were expressed at higher levels in early stage HCC compared to dysplasia and as compared with early stage HCC, lncRNA AK021443 level increase in advanced stage HCC while lncRNA AF070632 level decrease in advanced stage HCC. Using quantitative real-time reverse-transcription PCR, we validated that LINC01419 was significantly overexpressed in HBV-related and HCV-related HCC when compared with matched non-tumor liver tissues. Moreover, functional predictions suggested that LINC01419 and AK021443 regulate cell cycle genes, whereas AF070632 is associated with cofactor binding, oxidation-reduction and carboxylic acid catabolic process. These findings provide the first large-scale survey of lncRNAs associated with the development of hepatocarcinogenesis and may offer new diagnostic biomarkers and therapeutic targets for HCV-related HCC.

Coffee and cancer risk: A meta-analysis of prospective observational studies

Meta-analyses on coffee and cancer incidence mainly restricted to limited cancers. We carried out a more comprehensive meta-analysis of cohort studies to explore association between coffee and most cancer types. We conducted comprehensive search and summarized relative risk (RR) and 95% confidence intervals for the highest versus lowest coffee intake and cancer using STATA12. We conducted dose-analysis if result suggested significant association. The publication bias was evaluated with begg’s and egger’s test. Finally, 105 individual prospective studies were included. Inverse associations were observed on oral, pharyngeal, colon, liver, prostate, endometrial cancer and melanoma, with RR 0.69 (95% CI = 0.48–0.99, I2 = 73.4%, P = 0.044), 0.87 (95% CI = 0.78–0.96, I2 = 28.4%, P = 0.007), 0.46 (95% CI = 0.37–0.57, I2 = 0%, P = 0), 0.89 (95% CI = 0.84–0.93, I2 = 30.3%, P = 0.003), 0.73 (95% CI = 0.67–0.80, I2  = 0%, P = 0) and 0.89 (95% CI = 0.80–0.99, I2  = 0%, P = 0.031) respectively. However, the relative risk for lung cancer is 2.18 (95% CI = 1.26–3.75, I2  = 63.3%, P = 0.005). The summary relative risk for increment of 2 cups of coffee were RR = 0.73, 95% CI = 0.67–0.79 for liver cancer, RR = 0.97, 95% CI = 0.96–0.98 for prostate cancer and RR = 0.88, 95% CI = 0.85–0.92 for endometrial cancer. Accordingly, coffee intake was associated with reduced risk of oral, pharynx, liver, colon, prostate, endometrial cancer and melanoma and increased lung cancer risk.

PD-1/PD-L blockade in gastrointestinal cancers: lessons learned and the road toward precision immunotherapy

Gastrointestinal (GI) malignancies are the most prevalent tumors worldwide, with increasing incidence and mortality. Although surgical resection, chemotherapy, radiotherapy, and molecular targeted therapy have led to significant advances in the treatment of GI cancer patients, overall survival is still low. Therefore, alternative strategies must be identified to improve patient outcomes. In the tumor microenvironment, tumor cells can escape the host immune response through the interaction of PD-1 and PD-L, which inhibits the function of T cells and tumor-infiltrating lymphocytes while increasing the function of immunosuppressive T regulatory cells. The use of an anti-PD-1/PD-L blockade enables reprogramming of the immune system to efficiently identify and kill tumor cells. In recent years, the efficacy of PD-1/PD-L blockade has been demonstrated in many tumors, and this treatment is expected to be a pan-immunotherapy for tumors. Here, we review the signaling pathway underlying the dysregulation of PD-1/PD-L in tumors, summarize the current clinical data for PD-1/PD-L inhibitors in GI malignancies, and discuss road toward precision immunotherapy in relation to PD-1/PD-L blockade. The preliminary data for PD-1/PD-L inhibitors are encouraging, and the precision immunotherapy of PD-1/PD-L inhibitors will be a viable and pivotal clinical strategy for GI cancer therapy.

Citrus Fruit Intake Substantially Reduces the Risk of Esophageal Cancer: A Meta-Analysis of Epidemiologic Studies

AbstractMany epidemiologic studies indicate a potential association between fruit and vegetable intake and various cancers. The purpose of this meta-analysis is to investigate the association between citrus fruit intake and esophageal cancer risk. The authors conducted a comprehensive search on PubMed, EMBASE, and the Cochrane Library from inception until July 2014. Studies presenting information about citrus intake and esophageal cancer were analyzed. The authors extracted the categories of citrus intake, study-specific odds ratio or relative risk, and the P value and associated 95% confidence intervals for the highest versus lowest dietary intake of citrus fruit level. The association was quantified using meta-analysis of standard errors with a random-effects model. Thirteen case–control studies and 6 cohort studies were eligible for inclusion. Citrus intake may significantly reduce risk of esophageal cancer (summary odds ratio = 0.63; 95% confidence interval = 0.52–0.75; P = 0), without notable publication bias (intercept = −0.79, P = 0.288) and with significant heterogeneity across studies (I2 = 52%). The results from epidemiologic studies suggest an inverse association between citrus fruit intake and esophageal cancer risk. The significant effect is consistent between case–control and cohort studies. Larger prospective studies with rigorous methodology should be considered to validate the association between citrus fruits and esophageal cancer.

Combination treatment including targeted therapy for advanced hepatocellular carcinoma

Management of advanced hepatocellular carcinoma (HCC), one of the most lethal cancers worldwide, has presented a therapeutic challenge over past decades. Most patients with advanced HCC and a low possibility of surgical resection have limited treatment options and no alternative but to accept local or palliative treatment. In the new era of cancer therapy, increasing numbers of molecular targeted agents (MTAs) have been applied in the treatment of advanced HCC. However, mono-targeted therapy has shown disappointing outcomes in disease control, primarily because of tumor heterogeneity and complex cell signal transduction. Because incapacitation of a single target is insufficient for cancer suppression, combination treatment for targeted therapy has been proposed and experimentally tested in several clinical trials. In this article, we review research studies aimed to enhance the efficacy of targeted therapy for HCC through combination strategies. Combination treatments involving targeted therapy for advanced HCC are compared and discussed.

Dr.VIS v2.0: an updated database of human disease-related viral integration sites in the era of high-throughput deep sequencing.

Dr.VIS is a database of human disease-related viral integration sites (VIS). The number of VIS has grown rapidly since Dr.VIS was first released in 2011, and there is growing recognition of the important role that viral integration plays in the development of malignancies. The updated database version, Dr.VIS v2.0 (http://www.bioinfo.org/drvis or bminfor.tongji.edu.cn/drvis_v2), represents 25 diseases, covers 3340 integration sites of eight oncogenic viruses in human chromosomes and provides more accurate information about VIS from high-throughput deep sequencing results obtained mainly after 2012. Data of VISes for three newly identified oncogenic viruses for 14 related diseases have been added to this 2015 update, which has a 5-fold increase of VISes compared to Dr.VIS v1.0. Dr.VIS v2.0 has 2244 precise integration sites, 867 integration regions and 551 junction sequences. A total of 2295 integration sites are located near 1730 involved genes. Of the VISes, 1153 are detected in the exons or introns of genes, with 294 located up to 5 kb and a further 112 located up to 10 kb away. As viral integration may alter chromosome stability and gene expression levels, characterizing VISes will contribute toward the discovery of novel oncogenes, tumor suppressor genes and tumor-associated pathways.

Evolution of the mir-181 microRNA family

Mir-181 is an ancient microRNA (miRNA) gene family that originated in urochordata. Although their functions were subjected to extensive studies in recent years, their evolutionary process remains largely unknown. Here we systematically investigated the homologous genes of the mir-181 family by a sequence similarity search. Representative sequences of the mir-181 gene family were used to reconstruct their evolutionary history. Our results indicated that this family could have derived from multiple duplications, which include two rounds of whole genome duplications and one round of segmental replication. Functional annotation of the target genes of the mir-181 family suggested that this family could participate in some important biological processes including transcriptional and translational regulation, signaling transduction etc. This analysis presented a complex evolutionary dynamics for the origination of a miRNA gene family.

Mps1/TTK: a novel target and biomarker for cancer.

Abstract Monopolar spindle1 (Mps1, also known as TTK) is the core component of the spindle assembly checkpoint, which functions to ensure proper distribution of chromosomes to daughter cells. Mps1 is hardly detectable in normal organs except the testis and placenta. However, high levels of Mps1 are found in many types of human malignancies, including glioblastoma, thyroid carcinoma, breast cancer, and other cancers. Several Mps1 inhibitors can inhibit the proliferation of cancer cells and exhibit demonstrable survival benefits. Mps1 can be utilized as a new immunogenic epitope, which is able to induce potent cytotoxic T lymphocyte activity against cancer cells while sparing normal cells. Some clinical trials have validated its safety, immunogenicity and clinical response. Thus, Mps1 may be a novel target for cancer therapy. Mps1 is differentially expressed between normal and malignant tissues, indicating its potential as a molecular biomarker for diagnosis. Meanwhile, the discovery that it clearly correlates with recurrence and survival time suggests it may serve as an independent prognostic biomarker as well.

Distinct hepatitis B virus integration patterns in hepatocellular carcinoma and adjacent normal liver tissue.

Infection by the hepatitis B virus (HBV) is one of the main etiologies of hepatocellular carcinoma (HCC). During chronic infection, HBV DNA can integrate into the human genome, and this has been postulated as a possible mechanism of HBV‐induced HCC. In this study we used 2199 HBV integration sites from Dr.VIS v2.0 and mapped them to the human genome (hg19) to obtain viral integration sites (VIS) related to protein‐coding and non‐protein‐coding genes. In total, we found 1,377 and 767 VIS within close proximity to protein coding genes and noncoding genes, respectively. Genes affected more than two times included 23.1% of protein‐coding genes and 24.7% of long noncoding RNAs (lncRNA). Only 4.8% of VIS were shared between HCC and non‐tumor tissues. HBV integrations were more common in chromosomes 5, 8, 10, and 19 in HCC tissue and chromosomes 1 and 2 in non‐tumorous tissue. The number of integration sites on each chromosome correlated with the number of fragile sites in non‐tumorous tissue but not in HCC tissue. Functional enrichment analysis of the protein‐coding genes containing or in close proximity to HBV integration sites in HCC tissue showed an enrichment of cancer related gene ontology terms. Additionally, the most frequently associated lncRNA genes were related to telomere maintenance, protein modification processes, and chromosome localization. Thus, HBV may have preferred integration sites in the human genome that serve a critical role in HCC development. These results show that HCC treatment may benefit from the development of next generation anti‐viral therapies.