Description: Originating in the equatorial Pacific, the El Niño–Southern Oscillation (ENSO) has highly consequential global impacts, motivating the need to understand its responses to anthropogenic warming. In this Review, we synthesize advances in observed and projected changes of multiple aspects of ENSO, including the processes behind such changes. As in previous syntheses, there is an inter-model consensus of an increase in future ENSO rainfall variability. Now, however, it is apparent that models that best capture key ENSO dynamics also tend to project an increase in future ENSO sea surface temperature variability and, thereby, ENSO magnitude under greenhouse warming, as well as an eastward shift and intensification of ENSO-related atmospheric teleconnections — the Pacific–North American and Pacific–South American patterns. Such projected changes are consistent with palaeoclimate evidence of stronger ENSO variability since the 1950s compared with past centuries. The increase in ENSO variability, though underpinned by increased equatorial Pacific upper-ocean stratification, is strongly influenced by internal variability, raising issues about its quantifiability and detectability. Yet, ongoing coordinated community efforts and computational advances are enabling long-simulation, large-ensemble experiments and high-resolution modelling, offering encouraging prospects for alleviating model biases, incorporating fundamental dynamical processes and reducing uncertainties in projections. Key points Under anthropogenic warming, the majority of climate models project faster background warming in the eastern equatorial Pacific compared with the west. The observed equatorial Pacific surface warming pattern since 1980, though opposite to the projected faster warming in the equatorial eastern Pacific, is within the inter-model range in terms of sea surface temperature (SST) gradients and is subject to influence from internal variability. El Niño–Southern Oscillation (ENSO) rainfall responses in the equatorial Pacific are projected to intensify and shift eastward, leading to an eastward intensification of extratropical teleconnections. ENSO SST variability and extreme ENSO events are projected to increase under greenhouse warming, with a stronger inter-model consensus in CMIP6 compared with CMIP5. However, the time of emergence for ENSO SST variability is later than that for ENSO rainfall variability, opposite to that for mean SST versus mean rainfall. Future ENSO change is likely influenced by past variability, such that quantification of future ENSO in the only realization of the real world is challenging. Although there is no definitive relationship of ENSO variability with the mean zonal SST gradient or seasonal cycle, palaeoclimate records suggest a causal connection between vertical temperature stratification and ENSO strength, and a greater ENSO strength since the 1950s than in past centuries, supporting an emerging increase in ENSO variability under greenhouse warming.

Description: The prognosis for hepatocellular carcinoma (HCC) remains dismal in terms of overall survival (OS), and its molecular pathogenesis has not been completely defined. Here, we report that the expression of deubiquitylase USP7 is higher in human HCC tissues than in matched non-tumor tissues. Ectopic USP7 expression promotes the growth of HCC cells in vivo and in vitro . Mechanistically, USP7 overexpression fosters HCC cell growth by forming a complex with and stabilizing the TRIP12 protein, which induces constitutive p14 ARF ubiquitination. Clinically, USP7 overexpression is significantly correlated with a malignant phenotype, including larger tumor size, multiple tumor, poor differentiation, elevated α-fetoprotein (AFP), and microvascular invasion. Moreover, overexpression of USP7 and/or TRIP12 correlates with shorter OS and higher cumulative recurrence rates in HCC. Together, our results reveal that USP7 stabilizes TRIP12 by deubiquitination, thus constitutively inactivating p14 ARF and promoting HCC progression, and represents a novel marker for predicting prognosis and a potential therapeutic target for HCC. This article is protected by copyright. All rights reserved.

Description: Molecular pathogenesis of intrahepatic cholangiocarcinoma (iCCA) is poorly understood and its incidence continues to increase worldwide. Deficiency of MAPK kinase kinase 4 (MAP3K4) has been reported to induce epithelial-mesenchymal transition (EMT) process of placental and embryonic development, yet its role in human cancer remains unknown. Previously, we have found that MAP3K4 had somatic mutation in iCCA. Here, we sequenced all exons of MAP3K4 in 124 iCCA patients and identified 9 somatic mutations in 10 (8.06%) patients, especially in those with lymph node metastasis and intrahepatic metastasis. We also showed that mRNA and protein levels of MAP3K4 were significantly reduced in iCCA than paired nontumor tissues. Furthermore, knockdown of MAP3K4 in cholangiocarcinoma cells markedly enhanced cell proliferation and invasiveness in vitro and tumor progression in vivo , accompanied by a typical EMT process. In contrast, over-expression of MAP3K4 in cholangiocarcinoma cells obviously reversed EMT and inhibited cell invasion. Mechanistically, MAP3K4 functioned as a negative regulator of EMT in iCCA by antagonizing the activity of p38/NF-κB/snail pathway. We found that tumor-inhibitory effect of MAP3K4 was abolished by inactivating mutations. Clinically, a tissue microarray study containing 322 iCCA samples from patients revealed that low MAP3K4 expression in iCCA positively correlated with aggressive tumor characteristics, such as vascular invasion and intrahepatic or lymph node metastases, and was independently associated with poor survival and increased recurrence after curative surgery. Conclusions : MAP3K4, significantly down-regulated, frequently mutated and potently regulating EMT process in iCCA, was a putative tumor suppressor of iCCA. This article is protected by copyright. All rights reserved.

Description: Background: Organ site-specific metastasis is an ominous feature for most poor-prognostic hepatocellular carcinoma (HCC) patients. Cancer cell lines and animal models are indispensable for investigating the molecular mechanisms of organ specific tropism. However, till now, little is known about the drivers in HCC metastatic tropism, and also no effective way has been developed to block the process of tropistic metastasis. Methods: In this study, we established several monoclonal HCC cell lines from HCCLM3-RFP together with their xenograft models, and then analyzed their metastatic potentials and tropisms using in-vitro and in-vivo assays, and finally elucidated the driving forces of HCC tropistic metastases. Results: Six monoclonal cell lines with different organ site-specific tropism were established successfully. SPARC, VCAM1 and ANGPTL4 were found positively correlated with the potentials of lung metastasis, while ITGA1 had a positive relation to lymph node metastasis of enterocoelia. Conclusions: By our powerful platforms, HCC metastatic tropisms in clinic could be easily mimicked and recapitulated for exploring the bilateral interactions between tumor and its microenvironment, elucidating the drivers of HCC metastatic tropisms, and testing anti-cancer effects of newly developed agent in pre-clinical stage.

Description: Virus-induced hepatocarcinogenesis involves a series of histological developmental processes with the step-wise acquisition of several genetic changes that are necessary for the malignant transformation of hepatocytes. Although genetic alterations are known to be involved in the pathogenesis of hepatocellular carcinoma (HCC), little is known about the contributions of specific genes to this process. To gain insight into the genetic alterations involved in the neoplastic evolution from chronic hepatitis B virus infection to dysplastic nodules (DN) to HCC, we captured and sequenced the exomes of four DNA samples: one DN sample, two HCC samples and one control peripheral blood sample from a single HCC patient. Mutations in the UBE3C gene (encoding ubiquitin ligase E3C) were observed in both tumor tissues. Then, we resequenced the UBE3C gene in a cohort of 105 HCC patients and identified mutations in 17 out of total 106 (16.0%) HCC patients. The subsequent experiments showed that UBE3C promoted HCC progression by regulating HCC cells epithelial-mesenchymal transition. Clinically, a tissue microarray study of a cohort containing 323 HCC patients revealed that the overexpression of UBE3C in primary HCC tissues correlated with decreased survival (hazard ratio [HR] = 1.657, 95% confidence interval [CI] = 1.220-2.251, P = 0.001) and early tumor recurrence (HR = 1.653, 95% CI = 1.227-2.228, P = 0.001) in postoperative HCC patients. Conclusion : Our findings indicate that UBE3C is a candidate oncogene involved in tumor development and progression and therefore a potential therapeutic target in applicable HCC patients. (H epatology 2014;)

Description: Background: Sirtuin 3 (Sirt3), one of the seven Sirtuins family members, plays critical roles in the progression of multiple cancer types. However, its role in the prognosis of hepatocellular carcinoma (HCC) has not yet been investigated systematically. Methods: The correlation of Sirtuins expression with prognosis of HCC was determined by immunohistochemistry (IHC) in a large HCC patient cohort (n = 342). Expression of Sirt3 in tumoral and peritumoral tissues of HCC patients were further determined by western blotting (WB). Results: IHC and WB studies both showed a decreased expression of Sirt3 in tumoral tissues compared with peritumoral tissues (P = 0.003 for IHC, P = 0.0042 for WB). Decreased expression of Sirt3 in both tumoral and peritumoral tissues was associated with increased recurrence probability and decreased overall survival rate by univariate analyses (intratumoral Sirt3: P = 0.011 for TTR, P = 0.001 for OS; peritumoral Sirt3: P = 0.017 for TTR, P = 0.023 for OS), the prognostic value was strengthened by multivariate analyses (intratumoral Sirt3: P = 0.031 for TTR, P = 0.001 for OS; peritumoral Sirt3: P = 0.047 for TTR, P = 0.031 for OS). Intratumoral Sirt3 also showed a favorable prognostic value in patients with BCLC stage A (TTR, P = 0.011; OS, P 〈 0.001). In addition, we found that IHC studies of other sirtuin members showed a decreased expression of Sirt2, Sirt4 and Sirt5 and an increased expression of Sirt1, Sirt6 and Sirt7 in intratumoral tissues compared with peritumoral tissues. In contrast to Sirt3, other members did not showed a remarkable correlation with HCC prognosis. Conclusions: Down-regulation of intratumoral and peritumoral Sirt3 were both associated with poor outcome in HCC, moreover, intratumoral Sirt3 was a favorable prognostic predictor in early stage patients.

Description: Analytical Chemistry DOI: 10.1021/ac4027669

Description: Circulating microRNAs are promising biomarkers for non-invasive testing and dynamic monitoring in cancer patients. However, no consensus exists regarding the normalization of circulating microRNAs in the quantification, making the results incomparable. We investigated global circulating microRNA profiles to identify a stable endogenous control for quantifying circulating microRNAs using 3 cohorts (n=544), including 168 control individuals (healthy subjects and those with chronic hepatitis B and cirrhosis) and 376 cancer patients (hepatocellular, colorectal, lung, esophageal, gastric, renal, prostate, and breast cancer patients). GeNorm, NormFinder, and coefficient of variability (CV) were used to select the most stable endogenous control, whereas Ingenuity Pathway Analysis (IPA) was adopted to explore its signaling pathways. Seven candidates (miR-1225-3p, miR-1228, miR-30d, miR-939, miR-940, miR-188-5p, and miR-134) from microarray analysis and 4 commonly used controls (miR-16, miR-223, let-7a, and RNU6B) from literature were subjected to real-time quantitative reverse transcription-polymerase chain reaction validation using independent cohorts. MiR-1228 (CV=5.4%) with minimum M value and S value presented as the most stable endogenous control across 8 cancer types and 3 controls. IPA showed miR-1228 to be involved extensively in metabolism-related signal pathways and organ morphology, implying that miR-1228 functions as a housekeeping gene. Functional network analysis found that “hematological system development” was on the list of the top networks that associate with miR-1228, implying that miR-1228 plays an important role in the hematological system. The results explained the steady expression of miR-1228 in the blood. In conclusion, miR-1228 is a promising stable endogenous control for quantifying circulating microRNAs in cancer patients. © 2014 Wiley Periodicals, Inc.

Description: Endothelial cells (ECs) are critical for angiogenesis, and microRNA plays important roles in this process. In this study, we investigated the function and mechanism of miR-302c in the process of endothelial-mesenchymal transition (EndMT) in ECs. When miR-302c was overexpressed in HUVECs, the motility of the HUVECs was weakened; the expression levels of EndMT markers were also changed: vascular endothelial (VE)-cadherin was up-regulated, whereas β-catenin, FSP1, and α-SMA were down-regulated. Further in vivo and in vitro experiments showed that the growth of HCC was inhibited when co-cultured or co-injected with HUVECs overexpressing miR-302c. On the contrary, when miR-302c was suppressed in HUVECs, the opposite results were observed. Reporter assays showed that miR-302c inhibited metadherin (MTDH) expression through directly binding to its 3′UTR. In addition, compared to ECs isolated from normal liver tissues of HCC patients, ECs isolated from tumor tissues expressed markedly low levels of miR-302c but high levels of MTDH. These results suggest that EC-specific miR-302c suppresses tumor growth in HCC through MTDH-mediated inhibition of EndMT. MTDH and miR-302c might provide a new strategy for anti-angiogenic therapy in HCC. Scientific Reports 4 doi: 10.1038/srep05524

Description: BACKGROUND: Although the incidence of hepatitis B virus surface antigen (HBsAg)-negative/hepatitis C virus antibody (HCVAb)-negative hepatocellular carcinoma (NBNC-HCC) is gradually increasing, it has been mostly ignored in previous studies. The objective of this exploratory study was to investigate the clinicopathologic characteristics and prognostic factors that influence recurrence and survival in patients with NBNC-HCC. METHODS: A retrospective analysis was performed of 675 patients with NBNC-HCC and 3529 patients with HBsAg-positive/HCVAb-negative HCC (BNC-HCC) who underwent curative resection between 1997 and 2009. Intrahepatic recurrences were classified into early (≤1 year) and late (〉1 year) recurrences. Multivariate competing risks analyses with Bonferroni correction were used to evaluate independent prognostic factors. RESULTS: There were no significant differences between the NBNC-HCC and BNC-HCC groups regarding overall survival, cumulative incidence of HCC-specific death, and recurrence. However, the patients with NBNC-HCC were much older ( P 〈 .001), were associated less often with cirrhosis or elevated α-fetoprotein levels ( P 〈 .001), and had a much lower ratio of men to women ( P 〈 .001). NBNC-HCC tumors were larger ( P 〈 .001), but were involved less often with vascular invasion ( P = .004). Women, serum γ-glutamyl transpeptidase level, tumor size, tumor capsule, and tumor differentiation were identified as independent risk factors for HCC-specific survival in patients with NBNC-HCC. The cumulative incidence of HCC-specific death for women with NBNC-HCC was significantly greater than for men with NBNC-HCC ( P 〈 .001).Tumor capsule and vascular invasion were identified as independent risk factors for early recurrence of NBNC-HCC, whereas tumor differentiation was identified as the only significant risk factor for late recurrence. CONCLUSIONS: Patients who had NBNC-HCC had characteristics and prognostic factors that differed from those in patients who had BNC-HCC. Women with NBNC-HCC should be more closely monitored, and it may be worthwhile to evaluate estrogen administration for the maintenance of sex hormone balance and to improve these poor outcomes. Cancer 2012. © 2012 American Cancer Society.