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: We previously identified JWA as a novel microtubule-associated protein (MAP), which is implicated in carcinogenesis and tumor progression. The aims of the present study were to investigate the biological action and the prognostic significance of JWA in hepatocellular carcinoma (HCC). Quantitative real-time PCR and Western blot were used to detect JWA mRNA and protein expression, respectively, in stepwise metastatic HCC cell lines and HCC tissues. Short hairpin RNA was used to inhibit JWA expression in HCC cells. The effects of JWA depletion on cell migration, invasion, adhesion and in vivo metastasis were investigated. Immunohistochemistry of JWA was conducted in microarrays with tissue from 314 HCC patients who had undergone surgical resection. Prognostic significance was assessed using the Kaplan–Meier method and log-rank tests. The result showed JWA expression was decreased in the highly metastatic HCC cell lines and HCC tissues. Depletion of JWA caused a notable increase in cell migration, invasion and adhesion in vitro and metastasis in vivo. Furthermore, there was an inverse correlation between JWA expression and FAK expression and phosphorylation, RhoA activation and matrix metalloproteinase-2 (MMP-2) activity in HCC cells. More notably, multivariate analysis revealed that a low level of JWA expression was an independent prognosticator for both recurrence-free and overall survival for HCC patients after surgical resection, especially for AFP-normal HCC patients. Taken together, our data demonstrate that JWA plays a crucial role in HCC progression and suggest JWA may be a potential prognostic biomarker and therapeutic target for HCC. © 2012 Wiley Periodicals, Inc.

Description: Hypoxia inducible factors (HIFs) are activated in many tumors and show either promoter or suppressor activity depending on the tumor cell biology and background. However, the role of HIF member HIF-2α remains unclear in hepatocellular carcinoma (HCC). Here, HIF-2α expression was measured in HCC and paired peritumoral tissues by qRT-PCR, western blot analysis, and immunofluorescence assays, and the clinical significance was explored in 246 HCC patients. In cell culture, HIF-2α levels were over-expressed or knocked-down by use of expression or short hairpin RNA recombinant plasmid respectively. Cells were analyzed by immunoblot, chromatin immunoprecipitation coupled with microarray, co-immunoprecipitation, and histochemical staining. In vivo tumor growth was analyzed in nude mice. We found that the average expression of HIF-2α was relatively low in HCC tissues, and the decreased level was associated with lower overall survival (p=0.006). High HIF-2α expression in HCC cells induced higher levels of apoptosis and expression of pro-apoptotic proteins, and it inhibited cell and tumor growth. Furthermore, HIF-2α inhibited expression of the novel target gene transcription factor dimerization partner 3 (TFDP3). TFDP3 protein was found to bind with E2F transcription factor 1 (E2F1) and inhibit its transcriptional activity through both p53-dependent and -independent pathways. Re-introduction of TFDP3 expression reversed HIF-2α-induced apoptosis. Conclusions: Data gathered from cell lines, tumorigenicity studies, and primary HCC samples demonstrate a negative role of HIF-2α in tumors, which is mediated by the TFDP3/E2F1 pathway. Our study provides evidence supporting a possible tumor suppressor role for HIF-2α and has uncovered a mechanism that links HIF-2α to a fundamental biological regulator, E2F1. (H EPATOLOGY 2012.)

Description: HnRNP A1 is a member of the A/B subfamily of ubiquitously expressed hnRNPs, which have a wide variety of functions in gene expression and signal transduction. To investigate the biological function and clinical significance of hnRNP A1 in hepatocellular carcinoma (HCC), we measured hnRNP A1 expression in four HCC cell lines and two independent cohorts of HCC patients. We found that hnRNP A1 was overexpressed in the highly metastatic HCC cell lines and in tumor tissues of patients with recurrent HCC. Knockdown of hnRNP A1 in highly metastatic HCC cells caused a significant decrease in cell invasion, while up-regulation of hnRNP A1 in poorly metastatic HCC cells led to a significant increase in their invasive capacity. We found that this effect may occur through the regulation of CD44v6 expression by hnRNP A1 in HCC cells. Both qRT-RCR and immunohistochemistry revealed that hnRNP A1 was up-regulated in HCC tissues and coincided with overexpression of CD44v6. HCC patients with high hnRNP A1 tended to have higher levels of CD44v6, shorter overall survival, and higher rates of tumor recurrence. Multivariate analyses revealed that hnRNP A1 alone or in combination with CD44v6 were independent prognostic indicators for overall survival and time to recurrence and have potential as therapeutic targets. In conclusion, overexpression of hnRNP A1 promotes HCC invasion by regulating the level of CD44v6 and indicates a poor prognosis for HCC patients after curative resection.

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.

Description: CXCL5 (epithelial neutrophil-activating peptide-78) is a member of a proangiogenic subgroup of the CXC-type chemokine family of small, secreted proteins. Recently, evidence that CXCL5 is involved in carcinogenesis and cancer progression has emerged. To investigate the role of CXCL5 in tumor growth, invasion, and prognosis of hepatocellular carcinoma (HCC), we examined CXCL5 mRNA and protein levels in HCC cell lines with various metastatic potentials and in three independent cohorts of 919 HCC patients. We found that CXCL5 expression was increased in the highly metastatic HCC cell lines and in tumor tissues from patients with recurrent HCC compared to controls. CXCL5 activated the PI3K-Akt and ERK1/2 signaling pathways in HCC cells and promoted proliferation, migration, and invasion. Furthermore, we found that CXCL5 had a direct chemoattractant effect on neutrophils in vitro. In animal studies, the up-regulation of CXCL5 in HCC cells promoted tumor growth, lung metastasis, and intratumoral neutrophil infiltration. Conversely, down-regulation of CXCL5 in HCC cells reduced tumor growth, metastasis, and intratumoral neutrophil infiltration. Immunohistochemical analysis in HCC samples showed that overexpression of CXCL5 was well correlated with intratumoral neutrophil infiltration, shorter overall survival, and tumor recurrence. Multivariate analysis revealed that CXCL5 overexpression alone, or combined with the presence of intratumoral neutrophils, was an independent prognostic indicator for overall survival and cumulative recurrence. CONCLUSION: CXCL5 promotes HCC cell proliferation, invasion, and intratumoral neutrophil infiltration. CXCL5 overexpression, alone or combined with intratumoral neutrophil presence, is a novel prognostic predictor, and CXCL5 is a potential therapeutic target for HCC. (H EPATOLOGY 2012.)

Description: The overall survival of patients with hepatocellular carcinoma (HCC) remains poor, and the molecular pathogenesis remains incompletely defined in HCC. Here, we report that increased expression of αB-Crystallin in human HCC predicts poor survival and disease recurrence after surgery. Multivariate analysis identifies αB-Crystallin expression as an independent predictor for postoperative recurrence and overall survival. We unveil that elevated expression of αB-Crystallin promotes HCC progression in vivo and in vitro. We demonstrate that αB-Crystallin overexpression fosters HCC progression by inducing epithelial-mesenchymal transition (EMT) in HCC cells through activation of the ERK cascade, which can counteract the effect of sorafenib. αB-Crystallin complexes with and elevates 14-3-3ζ protein, leading to up-regulation of ERK1/2 activity. Moreover, overexpression of αB-Crystallin in HCC cells induces EMT progression through an ERK1/2/Fra-1/slug signaling pathway. Clinically, our data reveal that overexpression of both αB-Crystallin and 14-3-3ζ correlates with the HCC poorest survival outcomes, and sorafenib response is impaired in patients with αB-Crystallin overexpression. Conclusions: These data suggest that the αB-Crystallin-14-3-3ζ complex acts synergistically to promote HCC progression by constitutively activating ERK signaling. This study reveals αB-Crystallin as a potential therapeutic target for HCC and a biomarker for predicting sorafenib treatment response. (H EPATOLOGY 2013.)

Description: MicroRNAs (miRNAs) play a critical role in the regulation of tumor metastasis. The role of these molecules in hepatocellular carcinoma (HCC), however, has not been fully elucidated. In this study, we employed miRNA-sequencing and identified 22 miRNAs involved in HCC metastasis. One of these, miR-28-5p, was downregulated in HCCs. This downregulation correlated with tumor metastasis, recurrence, and poor survival. Biofunctional investigations revealed that miR-28-5p deficiency promoted tumor growth and metastasis in nude mice without altering the in vitro biological characteristics of HCC cells. Through gene expression profiles and bioinformatics analysis, we identified interleukin-34 (IL-34) as a direct target of miR-28-5p, and the effects of miR-28-5p deficiency on HCC growth and metastasis was dependent on IL-34-mediated tumor-associated macrophage (TAMs) infiltration. Moreover, we found that TAMs induced by miR-28-5p-IL-34 signaling inhibit miR-28-5p expression on HCC cells via transforming growth factor-β1 (TGF-β1), resulting in an miR-28-5p-IL-34-macrophage positive feedback loop. In clinical HCC samples, miR-28-5p levels were inversely correlated with IL-34 expression and the number of TAMs. Patients with low miR-28-5p expression, high IL-34 levels, and high numbers of TAMs had a poor prognosis with shorter overall survival (OS) and time to recurrence (TTR). Conclusion : an miR-28-5p-IL-34-macrophage feedback loop modulates HCC metastasis and serves as a novel prognostic factor as well as a therapeutic target for HCC. This article is protected by copyright. All rights reserved.

Description: Overexpression of interleukin-35 associates with hepatocellular carcinoma aggressiveness and recurrence after curative resection British Journal of Cancer 114, 767 (29 March 2016). doi:10.1038/bjc.2016.47 Authors: Yi-Peng Fu, Yong Yi, Xiao-Yan Cai, Jian Sun, Xiao-Chun Ni, Hong-Wei He, Jia-Xing Wang, Zhu-Feng Lu, Jin-Long Huang, Ya Cao, Jian Zhou, Jia Fan & Shuang-Jian Qiu

Description: Journal of Proteome Research DOI: 10.1021/acs.jproteome.6b00010