Transcription factor EHF drives cholangiocarcinoma development through transcriptional activation of glioma-associated oncogene homolog 1 and chemokine CCL2.

Cholangiocarcinoma (CCA) is characterized by rapid onset and high chance of metastasis. Therefore, identification of novel therapeutic targets is imperative. E26 transformation-specific homologous factor (EHF), a member of the E26 transformation-specific transcription factor family, plays a pivotal role in epithelial cell differentiation and cancer progression. However, its precise role in CCA remains unclear. In this study, through in vitro and in vivo experiments, we demonstrated that EHF plays a profound role in promoting CCA by transcriptional activation of glioma-associated oncogene homolog 1 (GLI1). Moreover, EHF significantly recruited and activated tumor-associated macrophages (TAMs) through the C-C motif chemokine 2/C-C chemokine receptor type 2 (CCL2/CCR2) axis, thereby remodeling the tumor microenvironment. In human CCA tissues, EHF expression was positively correlated with GLI1 and CCL2 expression, and patients with co-expression of EHF/GLI1 or EHF/CCL2 had the most adverse prognosis. Furthermore, the combination of the GLI1 inhibitor, GANT58, and CCR2 inhibitor, INCB3344, substantially reduced the occurrence of EHF-mediated CCA. In summary, our findings suggest that EHF is a potential prognostic biomarker for patients with CCA, while also advocating the therapeutic approach of combined targeting of GLI1 and CCL2/CCR2-TAMs to inhibit EHF-driven CCA development.

Myeloid-derived suppressor cells in cancer: therapeutic targets to overcome tumor immune evasion.

Paradoxically, tumor development and progression can be inhibited and promoted by the immune system. After three stages of immune editing, namely, elimination, homeostasis and escape, tumor cells are no longer restricted by immune surveillance and thus develop into clinical tumors. The mechanisms of immune escape include abnormalities in antitumor-associated immune cells, selection for immune resistance to tumor cells, impaired transport of T cells, and the formation of an immunosuppressive tumor microenvironment. A population of distinct immature myeloid cells, myeloid-derived suppressor cells (MDSCs), mediate immune escape primarily by exerting immunosuppressive effects and participating in the constitution of an immunosuppressive microtumor environment. Clinical trials have found that the levels of MDSCs in the peripheral blood of cancer patients are strongly correlated with tumor stage, metastasis and prognosis. Moreover, animal experiments have confirmed that elimination of MDSCs inhibits tumor growth and metastasis to some extent. Therefore, MDSCs may become the target of immunotherapy for many cancers, and eliminating MDSCs can help improve the response rate to cancer treatment and patient survival. However, a clear definition of MDSCs and the specific mechanism involved in immune escape are lacking. In this paper, we review the role of the MDSCs population in tumor development and the mechanisms involved in immune escape in different tumor contexts. In addition, we discuss the use of these cells as targets for tumor immunotherapy. This review not only contributes to a systematic and comprehensive understanding of the essential role of MDSCs in immune system reactions against tumors but also provides information to guide the development of cancer therapies targeting MDSCs.

Pan-cancer analysis of ABCC1 as a potential prognostic and immunological biomarker.

ABCC1 belongs to the ATP-binding cassette (ABC) superfamily, which encompasses a total of 48 constituent members. ABCC1 has been shown to be associated with the growth, progression, and drug resistance of various types of cancer. However, the impact of ABCC1 on cancer immune infiltration and pan-cancer prognosis has been rarely studied. Our comprehensive pan-cancer analysis unveiled elevated ABCC1 expression across various cancers. ABCC1 overexpression consistently predicted unfavorable outcomes based on TCGA data. Moreover, ABCC1 expression exhibited intricate associations with diverse immune-related genes and demonstrated a close correlation with immune scores across multiple tumor types. Analysis of scRNA-seq data from the GEO database revealed that the expression of ABCC1 in hepatocellular carcinoma (HCC) cells is significant positively correlated with macrophage infiltration. Furthermore, various in vitro and in vivo experiments substantiated the role of ABCC1 in promoting the progression of HCC, along with increased macrophage recruitment. Based on the results, we propose ABCC1 as a potentially valuable prognostic indicator and a prospective target for immune-based cancer therapies.

LINC01980 induced by TGF-beta promotes hepatocellular carcinoma metastasis via miR-376b-5p/E2F5 axis.

Hepatocellular carcinoma (HCC) is one of the most aggressive human malignancies worldwide. However, the molecular mechanism of HCC metastasis is largely unknown. Long non-coding RNA (lncRNA) plays a key role in gene regulation, and dysregulation of lncRNA is critical to cancer metastasis. LINC01980 has been reported in ESCC recently, but the mechanism underlying its function in HCC is still unknown. In this study, we found that LINC01980 was upregulated and associated with notably poor overall survival in HCC patients. Functionally, LINC01980 played a carcinogenic role and promoted HCC metastasis. Mechanically, LINC01980 enhanced the E2F5 expression via competitively binding miR-376b-5p, thereby inducing epithelial-mesenchymal transition and promoting HCC cells migration and invasion. In addition, LINC01980-mediated HCC cells metastasis was dependent on E2F5. What's more, TGF-ß activated LINC01980 transcription through the canonical TGF-ß/SMAD signaling pathway in HCC. In conclusion, LINC01980, activated by the canonical TGF-ß/SMAD pathway, promoted HCC metastasis via miR-376b-5p/E2F5 axis. Therefore, LINC01980 might be a potential prognostic biomarker and therapeutic target of HCC.

TRIM55 Promotes Proliferation of Hepatocellular Carcinoma Through Stabilizing TRIP6 to Activate Wnt/ß-Catenin Signaling.

Purpose: Tripartite motif containing 55 (TRIM55) is a member of the TRIM family and functions as an E3 ubiquitin ligase. It acts as a cancer promoter or suppressor in the malignant processes of multiple cancers. However, its proliferative function in hepatocellular carcinoma (HCC) has been poorly studied, and its underlying molecular mechanism remains unclear. In the present study, we investigated the role of TRIM55 in HCC and its mechanism of promoting HCC proliferation. Materials and Methods: Protein expression levels of TRIM55 were measured in paired HCC and normal tissue samples using immunohistochemical (IHC) staining. The correlation between TRIM55 and clinical features was evaluated by statistical analysis. At the same time, overexpression and knockdown experiments, cycloheximide (CHX) interference experiments, ubiquitination, co-immunoprecipitation and immunofluorescence staining experiments, as well as animal experiments were used to evaluate the potential mechanism that TRIM55 promotes proliferation of hepatocellular carcinoma in vitro and in vivo. Results: TRIM55 expression in HCC specimens was higher compared with the corresponding non-tumor tissues. The overall survival and disease-free survival time of patients with high TRIM55 expression were shorter than those with low expression of TRIM55. Functionally, TRIM55 promoted the proliferation of HCC cells and accelerated the growth of HCC xenografts. Mechanistically, TRIM55 interacted with thyroid receptor interacting protein 6 (TRIP6) and regulate its stability by influencing the ubiquitination process, thereby affecting the Wnt signaling pathway. Conclusion: Our results indicate that TRIM55 promotes HCC proliferation by activating Wnt signaling pathways by stabilizing TRIP6. Therefore, targeting TRIM55 may be an effective therapeutic strategy to inhibit HCC growth.

Ring finger protein 12 activates AKT signalling to promote the progression of liver cancer by interacting with EGFR.

Liver cancer is one of the most common solid tumours, and ranks as the third leading cause of cancer-associated mortality around the world. This study has linked RNF12 to the pathogenesis of liver cancer. Based on the analysis of patient samples and database data, high RNF12 expression was found in liver cancer, in correlation with worse clinicopathological features and a poor prognosis. Meantime, RNF12 could promote the progression of liver cancer in vitro and in vivo. Mechanistically, RNF12 could interact with EGFR and decrease the internalization of EGFR to activate EGF/EGFR signalling. In addition, PI3K-AKT signalling takes part in the regulation of liver cancer cell proliferation and migration of RNF12. And AKT inhibitor MK2206 could reverse RNF12-mediated cellular proliferation and migration in liver cancer. The possibility of the physical interaction between RNF12 and EGFR might lay a foundation to develop intervention strategies for liver cancer prevention and therapy.

Long noncoding RNA MAPKAPK5-AS1 promotes metastasis through regulation miR-376b-5p/ECT2 axis in hepatocellular carcinoma.

BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is one of the most common diseases threatening human health worldwide. However, the molecular mechanisms of HCC are still unclear. Here, we identified a differentially expressed lncRNA called MAPKAPK5-AS1(abbreviation: MK5-AS1) and elucidated its role and molecular mechanism in the development of HCC. METHODS: Real-time PCR (RT-PCR) was used to verify the expression of MK5-AS1 in hepatocarcinoma cell lines and tumor tissues of HCC patients. The biological functions of MK5-AS1 in HCC cells was assessed both in vitro and in vivo assays. The Lncbase, miRDB and TargetScan databases were used to predict the lncRNA-miRNA-mRNA interactions. RNA immunoprecipitation (RIP) and double luciferase reporter gene assays further verified the interactions. RESULTS: MK5-AS1 expression was significantly upregulated in HCC tissues and cell lines. Furthermore, high MK5-AS1 expression was positively associated with tumor progression and poor prognosis. In vitro and in vivo experiments confirmed that overexpressed MK5-AS1 promoted migration and invasion of HCC cells. Bioinformatics analysis based on Lncbase, miRDB and TargetScan databases showed MK5-AS1 competitively bound to miR-376b-5p that prevented epithelial cell transforming sequence 2 (ECT2) from miRNA-mediated degradation, thus facilitated HCC metastasis. CONCLUSION: Our results established a tumor promotive role of MK5-AS1 in HCC pathogenesis.

RHO GTPase family in hepatocellular carcinoma.

RHO GTPases are a subfamily of the RAS superfamily of proteins, which are highly conserved in eukaryotic species and have important biological functions, including actin cytoskeleton reorganization, cell proliferation, cell polarity, and vesicular transport. Recent studies indicate that RHO GTPases participate in the proliferation, migration, invasion and metastasis of cancer, playing an essential role in the tumorigenesis and progression of hepatocellular carcinoma (HCC). This review first introduces the classification, structure, regulators and functions of RHO GTPases, then dissects its role in HCC, especially in migration and metastasis. Finally, we summarize inhibitors targeting RHO GTPases and highlight the issues that should be addressed to improve the potency of these inhibitors.

Emerging roles of TRIM27 in cancer and other human diseases.

As a member of the TRIM protein family, TRIM27 is a RING-mediated E3 ubiquitin ligase that can mark other proteins for degradation. Its ubiquitination targets include PTEN, IκBα and p53, which allows it to regulate many signaling pathways to exert its functions under both physiological and pathological conditions, such as cell proliferation, differentiation and apoptosis. During the past decades, TRIM27 was reported to be involved in many diseases, including cancer, lupus nephritis, ischemia-reperfusion injury and Parkinson's disease. Although the research interest in TRIM27 is increasing, there are few reviews about the diverse roles of this protein. Here, we systematically review the roles of TRIM27 in cancer and other human diseases. Firstly, we introduce the biological functions of TRIM27. Next, we focus on the roles of TRIM27 in cancer, including ovarian cancer, breast cancer and lung cancer. At the same time, we also describe the roles of TRIM27 in other human diseases, such as lupus nephritis, ischemia-reperfusion injury and Parkinson's disease. Finally, we discuss the future directions of TRIM27 research, especially its potential roles in tumor immunity.

Pan-cancer analysis combined with experimental validation revealed IL4I1 as an immunological and prognostic biomarker.

Interleukin-4-induced gene 1 (IL4I1) is a secreted l-phenylalanine oxidase that deaminates phenylalanine to phenylpyruvate, releasing H2O2 and NH3 in the process. IL4I1 is mainly secreted by inflammatory antigen presenting cells and is involved in the regulation of adaptive immune responses. Furthermore, it has been reported that IL4I1 is overexpressed in a variety of tumor tissues and affects tumor development. We explored the expression patterns, correlation with clinical traits and prognostic value of IL4I1 using public databases and microarray data from sample banks. Subsequently, we used the downloaded data to score tumor stromal cells and immune cell infiltration and analyzed the correlation between IL4I1 and immune cells or immune-related molecules in combination with TIMER2.0 and GEPIA databases. The analysis showed that IL4I1 was associated with the infiltration status of various immune cells. Finally, stable IL4I1-overexpressing hepatocellular carcinoma (HCC) cell lines were established to investigate the effect of IL4I1 on cell proliferation and motor capacity. All of these results suggest that IL4I1 is a potential biomarker and therapeutic target.

TDO2 Was Downregulated in Hepatocellular Carcinoma and Inhibited Cell Proliferation by Upregulating the Expression of p21 and p27.

BACKGROUND: Tryptophan-2,3-dioxygenase (TDO2) converts tryptophan into kynurenine in the initial limiting step of the kynurenine pathway. During the past decade, the overexpression of TDO2 has been found in various human tumors. However, the role of TDO2 in hepatocellular carcinoma is controversial, and we sought to clarify it in this study. METHODS: Western blot analysis and immunochemistry were used to detect the expression of TDO2 in human tissue specimens. The effect of TDO2 on cell proliferation in vitro was assessed using CCK8 and colony formation assays, and a xenograft mouse model was used to detect the effect of TDO2 on tumor growth in vivo. Flow cytometry was used to assess the cell cycle status. RESULTS: Low TDO2 expression was found in HCC and was associated with poor prognosis and adverse clinical outcomes. Conversely, TDO2 could restrain the proliferation of HCC cells in vivo and in vitro. Furthermore, TDO2 upregulated the expression of p21 and p27, inducing cell-cycle arrest. CONCLUSIONS: The loss of TDO2 expression in HCC was correlated with a poor prognosis and adverse clinical outcomes. At the same time, TDO2 could restrain the growth of HCC in vivo and in vitro. The results indicate that TDO2 is a potential biomarker and therapeutic target for HCC.

The Emerging Roles of circFOXO3 in Cancer.

Circular RNAs (circRNAs) are a class of endogenous non-coding RNAs which are mainly formed by reverse splicing of precursor mRNAs. They are relatively stable and resistant to RNase R because of their covalently closed structure without 5' caps or 3' poly-adenylated tails. CircRNAs are widely expressed in eukaryotic cells and show tissue, timing, and disease specificity. Recent studies have found that circRNAs play an important role in many diseases. In particular, they affect the proliferation, invasion and prognosis of cancer by regulating gene expression. CircRNA Forkhead box O3 (circFOXO3) is a circRNA confirmed to be abnormally expressed in a variety of cancers, including prostate cancer, hepatocellular carcinoma, glioblastoma, bladder cancer, and breast cancer, etc. At present, the feature of circFOXO3 as a molecular sponge is widely studied to promote or inhibit the development of cancers. However, the diverse functions of circFOXO3 have not been fully understood. Hence, it is important to review the roles of circFOXO3 in cancers. This review has summarized and discussed the roles and molecular mechanism of circFOXO3 and its target genes in these cancers, which can help to enrich our understanding to the functions of circRNAs and carry out subsequent researches on circFOXO3.

Remediation potential of spent mushroom substrate on Cd pollution in a paddy soil.

To investigate the remediation potential of spent mushroom substrate (SMS) on Cd pollution in a paddy soil, a rice pot experiment was conducted to study the effects of SMS addition on the availability of Cd in soil and the uptake of Cd in rice tissues. Five percent of SMS from Pleurotus eryngii (SMS-A, treatment: A), SMS from Agaricus bisporus (SMS-B, treatment: B), or SMS-A plus SMS-B (1:1, treatment: A+B) were added into a Cd-contaminated paddy soil before planting, respectively. The treatment of no SMS amendment was set up as the control (CK). At the four main growth stages of rice, the soils and plant samples were collected to detect the soil properties, Cd concentration in soils and rice tissues, and Cd fractions in soils. Results indicated that the application of SMS-A, SMS-B, and A+B significantly increased soil pH by 14.0-22.9, 23.9-32.9, and 22.7-30%, organic matter (OM) contents by 12.9-31.5, 22.1-34.5, and 26.1-36.9% comparing with CK. While cation exchange capacities (CECs) were increased by 3.6-8.5, 4.9-13.1, and 0.4-10.0% in A, B, and A+B treatments, respectively, except those at the maturation stage in A and B treatments. However, the CaCl2-Cd concentrations in soils were significantly decreased by 64.8-77.9, 76.1-98.9, 73.2-98.9% in A, B, and A+B treatments, respectively, comparing with CK. The reduced availability of Cd was attributed to the changes of Cd from soluble to insoluble fractions in soils amended with SMS and resulted in the decreased Cd uptake in rice tissues. The Cd concentrations in roots significantly decreased by 22.8-36.9, 28.6-36.6, and 26.8-42.6%, while the Cd concentrations in straw decreased by 20.1-46.4, 9.3-41.6, and 16.0-49.1% in A, B, and A+B treatments, respectively. At the maturation stage, the Cd concentrations in brown rice were reduced by 17.7, 15.9, and 19.4% in A, B, and A+B treatments, respectively. Correlation analysis revealed that the Cd concentrations in rice roots, straws, and brown rice were all positively correlated with CaCl2-Cd concentrations of soils. Moreover, soil pH and OM were significantly negatively correlated with the Cd concentration in rice tissues, except that between soil pH and the Cd concentration in rice straws. Therefore, the reduced Cd availability in soil and uptake in rice plant tissues together with better soil nutrient conditions by SMS application improved the biomass of root and straw at heading, filling, and maturation stages and the rice production by 32.9-38.8% at the maturation stage. The combined application of SMS-A and SMS-B can be used as a potential method for remediation of Cd-contaminated paddy soil.

Capacity and potential mechanisms of Cd(II) adsorption from aqueous solution by blue algae-derived biochars.

The removal of potentially toxic metals by biochars is currently a popular and salutary method. In this study, we combined the advantages of blue algae (Microcystic) and pyrolysis technology to produce a late-model biochar. Moreover, the adsorption capacity and potential mechanisms of blue algae-derived biochars for the removal of cadmium (Cd) from aqueous solution were evaluated in comparison with the adsorption capacity and potential mechanisms of corn straw-derived biochar (CSBC) and rice husk-derived biochar (RHBC). Batch adsorption experiments were used to explore the adsorption performance of biochars, and a wide range of characterization techniques were employed: scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy and zeta potential analysis. The results showed that the adsorption isotherms could be described well by the Langmuir model and that the pseudo-second-order model fit the Cd(II) adsorption kinetics best, indicating that the process was monolayer and controlled by chemisorption. Moreover, the Cd(II) removal capacity of optimal blue algae-derived biochar (BC600-2) (135.7 mg g-1) was 85.9% and 66.9% higher than the removal capacity of CSBC and RHBC, respectively. In addition, the results of the characterization methods showed that precipitation with minerals was the primary mechanism, accounting for 68.7-89.5% of the capacity. Overall, blue algae-derived biochars, as a product from freshwater biowaste, may be a novel and potentially valuable adsorbent for Cd(II) removal.

LncRNA influence sequential steps of hepatocellular carcinoma metastasis.

As a class of new and crucial molecules involved in the regulation of biological function, long noncoding RNA (lncRNA) have obtained widespread attention in recent days. While it was thought that lncRNA would be redundant in the past, it is proved that lncRNA identify a class of molecular that regulate the homeostasis including hepatocellular carcinoma in the present. All kinds of lncRNA have been implicated in a various of diseases, particularly in tumorigenesis and metastasis. But the mechanisms how they act is still not entirely clear. Metastasis is a major factor affecting long-term survival in hepatocellular carcinoma (HCC) patients. Recently, growing numbers of experiments demonstrate that there is close connection between lncRNA and HCC metastasis. Here, we will briefly introduce a series of steps (primary tumor growth, angiogenesis, epithelial-to-mesenchymal transition, invasion, intravasation, survival in circulatory system, extravasation, dormancy and subsequent secondary tumor growth) of tumor metastasis, its classical but promising theories, the role of lncRNA in metastasis and the possible mechanisms involved. LncRNA, as potentially new and important tumor diagnostic and therapeutic molecules, has attracted much attention in recent years.