Erbin interacts with c-Cbl and promotes tumourigenesis and tumour growth in colorectal cancer by preventing c-Cbl-mediated ubiquitination and down-regulation of EGFR.

The epidermal growth factor receptor (EGFR) is implicated in many types of cancer, including colorectal cancer (CRC), and has become one of the most common candidates for targeted therapy. Here, we found that Erbin, a member of the leucine-rich repeat and PDZ domain (LAP) family, plays a key role in EGFR signalling. Erbin inhibited EGFR ubiquitination and stabilized the EGFR protein by interacting with c-Cbl. Moreover, the PDZ domain of Erbin was critical for the interaction between Erbin and c-Cbl and EGFR ubiquitination. Interestingly, Erbin expression was elevated in tumour samples from CRC patients, increased in advanced clinical stage disease and correlated with EGFR expression. In vivo studies using mouse xenograft models of CRC showed that Erbin promotes tumour growth, and that the effects of Erbin on tumour growth are mainly related to the regulatory effects of Erbin on EGFR. The azoxymethane (AOM)-induced colon carcinogenesis model in Erbin(ΔC) (/) (ΔC) mice, with the PDZ domain of Erbin deleted, demonstrated that the PDZ domain of Erbin and its regulation of EGFR signalling are necessary for the tumourigenesis and tumour growth of CRC. We found that Erbin promotes tumourigenesis and tumour growth in CRC by stabilizing EGFR. Our study sheds light on developing Erbin, especially its PDZ domain, as a potential target for CRC treatment.

An epigenetic role for PRL-3 as a regulator of H3K9 methylation in colorectal cancer.

OBJECTIVE: This study investigated the epigenetic role of PRL-3, a key metastasis gene in colorectal cancer (CRC), as a regulator of histone demethylation and the functions of Jumonji domain-containing protein 1B (JMJD1B) and JMJD2B in the progression of CRC. METHODS: PRL-3-associated proteins were analysed using functional distribution and category enrichment analysis. Western blotting and immunofluorescence were used to detect nuclear PRL-3. The relationship between PRL-3 and JMJD1B or JMJD2B and the roles of JMJD1B, JMJD2B and PRL-3 in histone demethylation were determined after these proteins were knocked down using RNA interference. Case-control studies on JMJD1B and JMJD2B in patients with CRC were performed using immunohistochemical analysis. The in vitro functional effects of JMJD2B and JMJD1B were examined further. RESULTS: JMJD1B and JMJD2B, two histone demethylases, were enriched among PRL-3-associated proteins. Nuclear PRL-3 was observed in CRC cells and clinical samples of CRC. The expression of nuclear PRL-3 was increased in patients with CRC at more advanced Dukes' stages. PRL-3 was involved in the regulation of histone methylation by affecting the activities of JMJD1B and JMJD2B. A low expression of the JMJD1B protein was positively correlated with the lymph node status (p=0.032), Dukes' classification (p=0.008) and TNM staging (p=0.022) of patients with CRC. A high expression of JMJD2B was positively correlated with the lymph node status (p=0.03), Dukes' classification (p=0.036) and tumour invasion (p=0.003) of patients with CRC. A loss-of-function analysis confirmed that JMJD2B promoted the proliferation, colony formation and migration of human CRC cells. CONCLUSION: Our data reveal a new role for PRL-3 as a key regulator of histone demethylation. JMJD1B seems to be a candidate tumour suppressor and JMJD2B seems to be a potential oncoprotein in the development and progression of CRC.

A bifunctional surfactant-like electrolyte additive for a stable lithium metal anode.

Nonafluorobutanesulfonyl fluoride (NtF) was developed as a bifunctional additive for enhancing the stability of the lithium metal anode. NtF can yield Nt+ and LiF. The presence of lithiophobic and lithiophilic groups in Nt+ facilitates the uniform deposition of Li+, while LiF contributes to forming a stable solid electrolyte interphase.

Talc as Dynamic Zincophilic Sites Enables Highly Reversible Zinc Metal Anodes.

Zinc (Zn) dendrite growth poses a significant challenge to the reversibility of zinc metal anodes (ZMAs). Traditional methods using fixed zincophilic sites often suffer from coverage issues and deactivation over time or under high areal capacities. To address this, we introduced Talc into a conventional ZnSO4-based electrolyte (BE + Talc), which acts as a dynamic zincophilic site. Talc effectively adsorbs and carries Zn2+ in the electrolyte, facilitating their co-deposition at the anode. After deposition, Talc re-enters the electrolyte, maintaining its functionality and counteracting the deactivation of static zincophilic sites. This approach resulted in a Zn-Zn symmetric cell using BE + Talc, achieving stable cycling for 200 h under rigorous conditions of 10 mA cm-2 and 5 mAh cm-2. Additionally, the Zn-Cu half-cell demonstrated over 1200 stable cycles at 5 mA cm-2 and 1 mAh cm-2. The Zn-NH4V4O10 full cell with Talc cycled for 200 cycles under practical conditions (4.5 mg cm-2, 10 µm Zn foil, and N/P ratio of 3.4) achieved a capacity retention rate of 82.7%. This study highlights the drawbacks of conventional zincophilic sites and presents an effective solution for achieving highly reversible ZMAs.

Fullerenol as a nano-molecular sieve additive enables stable zinc metal anodes.

Aqueous zinc batteries (AZBs) with the advantages of safety, low cost, and sustainability are promising candidates for large-scale energy storage devices. However, the issues of interface side reactions and dendrite growth at the zinc metal anode (ZMA) significantly harm the cycling lifespan of AZBs. In this study, we designed a nano-molecular sieve additive, fullerenol (C60(OH)n), which possesses a surface rich in hydroxyl groups that can be uniformly dispersed in the aqueous solution, and captures free water in the electrolyte, thereby suppressing the occurrence of interfacial corrosion. Besides, fullerenol can be further reduced to fullerene (C60) on the surface of ZMA, holding a unique self-smoothing effect that can inhibit the growth of dendritic Zn. With the synergistic action of these two effects, the fullerenol-contained electrolyte (FE) enables dendrite-free ZMAs. The Zn-Ti half-cell using FE exhibits stable cycling over 2500 times at 5 mA cm-2 with an average Coulombic efficiency as high as 99.8 %. Additionally, the Zn-NaV3O8 cell using this electrolyte displays a capacity retention rate of 100 % after 1000 cycles at -20 °C. This work provides important insights into the molecular design of multifunctional electrolyte additives.

Stathmin, a new target of PRL-3 identified by proteomic methods, plays a key role in progression and metastasis of colorectal cancer.

To better understand the role of PRL-3 in progression and metastasis of colorectal cancer (CRC), we searched for PRL-3 associated proteins using proteomic methods. We identified 39 PRL-3 associated proteins based on proteomic strategy. Stathmin, a key oncoprotein, was proved to be a new PRL-3 associated protein. Notably, co-immunoprecipitation assays in both endogenous CRC cell lines and CRC tissues indicated that PRL-3 could interact with stathmin. And, both stathmin and PRL-3 contributed to microtubule (MT) destabilization of CRC cells. Moreover, gain-of-function and loss-of-function analyses revealed that stathmin promoted proliferation, cell adhesion, and migration of human CRC cells. Immunohistochemical analysis of 149 colorectal tumor samples showed that overexpression of stathmin was strongly correlated with tumor differentiation (P = 0.035), tumor invasion (P = 0.024), lymph node status (P < 0.001), Dukes classification (P < 0.001), and TNM staging (P < 0.001) of CRC patients. Univariate and multivariate survival analyses further supported that overexpression of stathmin protein was a potential independent poor prognostic factor for CRC. Our results reveal many PRL-3 associated proteins for the first time. The oncoprotein stathmin plays a key role in CRC as a new target of PRL-3. Interaction between PRL-3 and stathmin leads to MT destabilization of CRC cells, which contributes to progression and metastasis of CRC.

The association between tumor necrosis factor alpha promoter polymorphisms and ankylosing spondylitis: a meta-analysis.

BACKGROUND: Studies investigating the association between tumor necrosis factor (TNF)-alpha promoter polymorphisms and ankylosing spondylitis have reported conflicting results. We here performed a meta-analysis based on the evidence currently available from the literature to make a more precise estimation of this relationship. METHODS: We performed a systematic search of the National Library of Medline and Embase databases before January 2013. This meta-analysis included 14 case-control studies, which included 1607 ankylosing spondylitis cases and 1910 controls. RESULTS: The combined results based on all studies showed that ankylosing spondylitis cases had a significantly lower frequency of -308GA [OR (codominant model)=0.81, 95% CI=0.66, 0.99, P=0.04], -857CT [OR (codominant model)=0.55, 95% CI=0.32, 0.94, P=0.03], -863AA [OR (codominant model)=0.11, 95% CI=0.01, 0.94, P=0.04], -863CA [OR (codominant model)=0.32, 95% CI=0.18, 0.58, P<0.001], and -1031TC [OR (codominant model)=0.44, 95% CI=0.25, 0.77, P=0.004] genotype. However, ankylosing spondylitis cases had a significantly higher frequency of -238AA [OR (recessive model)=7.43, 95% CI=3.66, 15.05, P<0.001] and -850TT [OR (recessive model)=2.49, 95% CI=1.16, 5.34, P=0.02; OR (codominant model)=2.83, 95% CI=1.28, 6.25, P=0.01] genotype. In the subgroup analysis by race, we found that ankylosing spondylitis cases had a significantly higher frequency of -238AA [OR (recessive model)=7.43, 95% CI=3.66, 15.05, P<0.001] genotype in Caucasians and lower frequency of -857CT [OR (codominant model)=0.53, 95% CI=0.30, 0.94, P=0.03] in Asians. CONCLUSIONS: Our meta-analysis suggests that TNF-alpha promoter polymorphisms at positions -238, -308, -850, -857, -863 and -1031 could have a small influence on ankylosing spondylitis susceptibility. But there is a lack of association of the TNF-alpha-376G/A and -646G/A polymorphisms with ankylosing spondylitis.

A signature for induced pluripotent stem cell-associated genes in colorectal cancer.

Genes associated with induced pluripotent stem cells (iPS genes) are several pivotal transcriptional factors, which are used to induce pluripotent stem cells from some adult somatic cells. The roles of these iPS genes and especially the signature for these iPS genes in colorectal cancer (CRC) are still unclear. Overexpressed Oct4 and Lin28 but down-regulated Nanog were found in tumor tissues compared with that in their paired normal counterparts of CRC patients. Interestingly, we found that Oct4, Lin28 and Nanog were highly overexpressed in some patients. And the signature for iPS genes was correlated with tumor site (P = 0.012), lymph node status (P = 0.033), Dukes classification (P = 0.033) of CRC patients. Moreover, an independent public expression profiling data showed signature for the four iPS genes could successfully be used to predict the survival of CRC patients with Dukes stages B and C. Immunofluorescent staining of fresh CRC tissues from patients showed that strong co-expressions of Oct4 and Nanog proteins or Sox2 and Lin28 were present in some CRC cells. Then, CRC cell subclone with four iPS genes overexpression were establish by a mixed retroviral system. We found that iPS genes promote sphere-formation, proliferation, colony formation, migration of human CRC cells in vitro and tumor growth in vivo. Our study first shows the clinical significance of iPS signature in CRC patients.

Snail as a key regulator of PRL-3 gene in colorectal cancer.

The regulators of a key metastasis gene PRL-3 in colorectal cancer (CRC) are still largely unknown. We found three potential binding sites of Snail, a key transcriptional factor involved in the epithelial-mesenchymal transition (EMT), in the region of PRL-3 promoter (located at -642 to -383). Moreover, our results showed that one of the Snail binding sites (located at -624 to -619) was the key element to maintain promoter activity of human PRL-3 gene. The transcriptional activity of PRL-3 promoter was abolished after the Snail binding site (located at -624 to -619) was mutated. Both promoter activity and protein expression of PRL-3 in CRC cell lines could be regulated by Snail. In clinical samples of CRC and metastatic lymph node of CRC, expression of PRL-3 protein was correlated with expression of Snail protein. Functional studies using gene over-expression and knockdown methods indicated that Snail promoted proliferation, cell adhesion and migration of human CRC cells. In SW480 cells with PRL-3 stable knockdown, cell proliferation increased after Snail was up-regulated. Our data first reveal transcriptional factor Snail as a key regulator of PRL-3 in CRC. The link between Snail and PRL-3 suggests a new potential mechanism of Snail contributing to progression and metastasis of CRC.