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Liver cancer represents a significant global burden in terms of cancer-related mortality, with resistance to anti-angiogenic drugs such as Sorafenib and Lenvatinib presenting a formidable challenge. Tumor angiogenesis, characterized by the formation of new blood vessels within tumors, plays a pivotal role in cancer progression and metastasis. Tumor endothelial cells, specialized endothelial cells lining tumor blood vessels, exhibit unique phenotypic and functional traits that drive aberrant vessel formation and contribute to therapy resistance. CD105, a cell-surface glycoprotein that is highly expressed on endothelial cells during angiogenesis, including tumor endothelial cells, regulates endothelial cell proliferation, migration, and vessel formation by modulating transforming growth factor-beta (TGF-β) signaling pathways. Elevated CD105 expression on tumor endothelial cells correlates with increased angiogenic activity and poor prognosis in cancer patients. Targeting CD105 with antibodies presents a promising strategy to inhibit tumor angiogenesis and disrupt tumor vasculature, offering potential therapeutic benefits by interfering with the tumor microenvironment and inhibiting its progression. This study investigates tumor angiogenesis through a three-dimensional (3D) microfluidic co-culture system incorporating endothelial cells and hepatocellular carcinoma (HCC) cells. The primary focus is on the role of CD105 expression within the liver tumor microenvironment and its contribution to increased chemoresistance. Additionally, this research examines the influence of CD105 expression on the efficacy of tyrosine kinase inhibitors (TKIs) and its pivotal function in facilitating angiogenesis in liver tumors. The proposed microfluidic chip model investigates liver cancer cell interactions within a microfluidic chip model designed to simulate aspects of liver tumor angiogenesis. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is a global health concern, necessitating adjuvant chemotherapy post-curative surgery to mitigate recurrence and enhance survival, particularly in intermediate-stage patients. However, existing therapeutic disparities highlight the need for biomarker-guided adjuvant chemotherapy to achieve better CRC inhibition. This study explores the molecular mechanisms underlying the inhibition of CRC through a genome-wide association study (GWAS) focused on 5-fluorouracil (5-FU)-based adjuvant therapy in intermediate-stage CRC patients, a domain previously unexplored. We retrospectively included 226 intermediate-stage CRC patients undergoing surgical resection followed by 5-FU-based adjuvant chemotherapy. The exploration cohort comprised 31 patients, and the validation cohort included 195 individuals. Genotyping was carried out using either Axiom Genome-Wide TWB 2.0 Array Plate-based or polymerase chain reaction-based methods on genomic DNA derived from collected tissue samples. Statistical analyses involved descriptive statistics, Kaplan–Meier analyses, and Cox proportional hazard analyses. From the GWAS, potential genetic predictors, GALNT14-rs62139523 and DNMBP-rs10786578 genotypes, of 5-FU-based adjuvant therapy following surgery in intermediate-stage CRC patients were identified. Validation in a larger cohort of 195 patients emphasized the predictive significance of GALNT14-rs62139523 genotypes, especially the "A/G" genotype, for improved overall and progression-free survival. This predictive association remained robust across various subgroups, with exceptions for specific demographic and clinical parameters such as age < 58 years old, CEA ≤ 2.5 ng/mL, tumor diameter > 44.0 mm, and tumor-free margin ≥ 50 mm. This study identifies that the GALNT14-rs62139523 "A/G" genotype modulates therapeutic outcomes, establishing it as a promising biomarker for predicting favorable responses to 5-FU-based adjuvant chemotherapy in intermediate-stage CRC patients, although further investigations are needed to detail these mechanisms. [ABSTRACT FROM AUTHOR]

Simple Summary: Gut dysbiosis with an impaired intestinal barrier is differentially associated with liver diseases and, therefore, alters the systemic immunological milieu through the gut–liver axis. As a result, it plays a prominent role in liver inflammation, fibrosis, and carcinogenesis. Here, a list of network features common to patients with liver cirrhosis or hepatocellular carcinoma (HCC), regardless of etiology, was identified. In addition, disease-specific signatures were identified. This study provides novel insights that suggest alterations in gut microbial/viral composition may either confer pre-HCC disorders or contribute to the metabolic reprogramming and/or inflammatory microenvironment for HCC development. Gut bacterial/viral dysbiosis, changes in circulating metabolites, and plasma cytokines/chemokines have been previously associated with various liver diseases. Here, we analyzed the associations between fecal microbial composition, circulating metabolites, and plasma cytokines/chemokines in patients with liver cirrhosis (LC) and hepatocellular carcinoma (HCC). We recruited 10 HCC patients, 18 LC patients, and 17 healthy individuals. Their stool samples were used for gene sequencing of bacterial 16S rRNA and viral genomes, while plasma samples were utilized for the determination of endotoxin, zonulin, metabolite, and cytokine/chemokine levels. Dysbiosis was observed among gut bacteria and viruses, with significant changes in abundance at the genus and species levels, respectively. However, no differences were found between cohorts in the alpha and beta diversity. Plasma lipopolysaccharides and zonulin, but not trimethylamine N-oxide, were progressively increased in LC and HCC subjects. Profiling plasma metabolites and selected cytokines/chemokines revealed differential changes in the LC and HCC cohorts. Following joint correlation and correlation network analyses, regardless of etiology, common network signatures shared by LC and HCC patients were characterized by the gut virus Stenotrophomonas virus DLP5 and the uncultured Caudovirales phage, plasma metabolites pyruvic acid and acetic acid, and plasma cytokines/chemokines eotaxin and PDGF-AB/BB, respectively. Additionally, LC- and HCC-specific correlation networks were also identified. This study provides novel insights into altered gut microbial/viral composition that may contribute to pre-HCC disorders, metabolic reprogramming, or inflammatory microenvironments for hepatocarcinogenesis. [ABSTRACT FROM AUTHOR]

Abstract: Background and Aim: Commonly used non‐invasive fibrosis scores usually included serum transaminase levels in the equations, including Aspartate transaminase to Platelet Ratio Index (APRI) and fibrosis‐4 (FIB‐4). Transaminases fluctuated significantly in chronic hepatitis B patients with exacerbations, leading to unsteady score values. As such, here, we aim to develop a transaminase‐free score suitable for pretherapeutic evaluation of fibrosis stages. Methods: Firstly, 1082 treatment‐naïve chronic hepatitis B patients were enrolled and divided into modeling (n = 541) and verification (n = 541) cohorts. Secondly, 265 patients having received liver biopsy, with known Ishak fibrosis stages, were included for independent correlation. Results: Cross‐sectional analysis of 1082 patients revealed age‐dependent variation of association between virological factors and cirrhosis. A fibrosis score including Anti‐hepatitis B e antibody, Basal core promoter (BCP) A1762T mutation, and Platelet count Index (named ABPI) was derived from the modeling cohort. ABPI performed better than APRI and FIB‐4 in the verification cohort for identifying cirrhotic patients (comparison of area under the receiver operating characteristic curves: ABPI vs APRI and FIB‐4 = 0.785 vs 0.563 [P < 0.001] and 0.700 [P = 0.026], respectively). The performance of ABPI was even better in young (< 40 years old) hepatitis B patients (area under the receiver operating characteristic curves: 0.856 vs 0.402 [P < 0.001] and 0.599 [P = 0.009], respectively). Finally, in the independent cohort of 265 patients with known Ishak fibrosis stages, it was found that ABPI effectively distinguished between Ishak fibrosis stages 3 and > 3 and between 4 and > 4 (P < 0.001 for each). Conclusions: We developed a transaminase‐free fibrosis score (ABPI) utilizing basal core promoter A1762T data, which outperformed APRI and FIB‐4. [ABSTRACT FROM AUTHOR]

Abstract: Aim: A genome‐wide association study (GWAS) had identified a single nucleotide polymorphism (SNP), GALNT14‐rs9679162, capable of predicting chemotherapy responses in advanced hepatocellular carcinoma (HCC). Here, we revisited the GWAS database to search for necessary SNPs that could improve our outcome prediction. Methods: A cohort of 116 HCC patients receiving split‐dose chemotherapy composed of 5‐fluorouracil, mitoxantrone and cisplatin was enrolled. The GALNT14‐rs9679162 together with four other leading candidate SNPs (rs6025211, rs715171, LOC105369482‐rs1955024 and WWOX‐rs13338697) was genotyped and correlated with time‐to‐tumor progression (TTP) and overall survival (OS). Results: GALNT14‐rs9679162‐TT genotype remained an effective predictor for favorable TTP and OS (P = 0.012 and 0.002). Additionally, it was found that WWOX‐rs13338697‐CT genotype was associated with unfavorable TTP (P = 0.031), independent of GALNT14‐rs9679162 genotype (adjusted P = 0.045), and rs6025211‐CT genotype was associated with unfavorable OS (P = 0.014), independent of GALNT14‐rs9679162 genotype (adjusted P = 0.025). Combinations of these SNPs stratified patients into three groups with differential treatment outcomes. Patients with GALNT14‐rs9679162‐TT/WWOX‐rs13338697‐non‐CT genotypes achieved the most favorable treatment outcomes (n = 19; median TTP, median OS and response rate were 3.9 months, 6.8 months and 4/19 [21.1%], respectively); whereas patients with GALNT14‐rs9679162‐non‐TT/rs6025211‐CT genotypes associated with the most unfavorable treatment outcomes (n = 40; median TTP, median OS and response rate were 1.9 months, 3.5 months and 1/40 [2.5%], respectively). The remaining patients constituted a third subgroup with intermediate clinical outcomes. Conclusions: Three genetic variants, GALNT14‐rs9679162, WWOX‐rs13338697 and rs6025211, stratified advanced HCC patients into three groups with differential treatment outcomes. [ABSTRACT FROM AUTHOR]

Oxidative phosphorylation (OXPHOS) consists of four enzyme complexes and ATP synthase, and is crucial for maintaining physiological tissue and cell growth by supporting the main bioenergy pool. Cytochrome c oxidase (COX) has been implicated as a primary regulatory site of OXPHOS. Recently, COX subunit 5B (COX5B) emerged as a potential biomarker associated with unfavorable prognosis by modulating cell behaviors in specific cancer types. However, its molecular mechanism remains unclear, particularly in colorectal cancers (CRCs). To understand the role of COX5B in CRCs, the expression and postoperative outcome associations using independent in-house patient cohorts were evaluated. A higher COX5B tumor/nontumor expression ratio was associated with unfavorable clinical outcomes (p = 0.001 and 0.011 for overall and disease-free survival, respectively. In cell-based experiments, the silencing of COX5B repressed cell growth and enhanced the susceptibility of CRCs cells to anticancer drugs. Finally, downstream effectors identified by RNA sequencing followed by RT-qPCR and functional compensation experiments revealed that the tight junction protein Claudin-2 (CLDN2) acts downstream of COX5B-mediated bioenergetic alterations in controlling cell growth and the sensitivity to anticancer drugs in CRCs cells. In conclusion, it was found that COX5B promoted cell growth and attenuated anticancer drugs susceptibility in CRCs cells by orchestrating CLDN2 expression, which may contribute to unfavorable postoperative outcomes of patients with CRCs. [ABSTRACT FROM AUTHOR]

Background/aim: Extra-thyroid expression of thyroid stimulating hormone (TSH) receptor (TSHR) has been reported in normal liver tissues, but never assessed in hepatocellular carcinoma (HCC)., Patients and Methods: Paired cancerous and non-cancerous HCC tissues were analyzed with TSHR expression assays. TSHR functional assessments and sequence analysis for the TSHR exon-10 were performed., Results: TSHR overexpression was found in 150/197 (76.1%) HCCs. Higher TSHR expression was associated with unfavorable postoperative outcomes. Immunohistochemical analysis revealed predominantly nuclei/peri-nuclei localization of TSHR in cancerous tissues but cell membrane localization in non-cancerous parts. TSH stimulation on hepatoma cells resulted in increased cyclic adenosine monophosphate levels with altered cell sensitivity to cisplatin. Gene mutations leading to TSHR truncation were detected in 8/81 (9.9%) HCC tissues., Conclusion: Overexpression of TSHR was found in a great majority of HCC tissues and associated with unfavorable prognosis. Cell-based experiments and gene mutation analysis suggested that TSHR in HCCs was functional., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The let-7 microRNA (miRNA) regulates cell cycle exit and terminal differentiation in the C. elegans heterochronic gene pathway. Low expression of let-7 results in retarded vulva and hypodermal cell development in C. elegans and has been associated with several human cancers. Previously, the versatile scaffold protein receptor for activated C kinase 1 (RACK1) was proposed to facilitate recruitment of the miRNA-induced silencing complex (miRISC) to the polysome and to be required for miRNA function in C. elegans and humans. Here, we show that depletion of C. elegans RACK-1 by RNAi increases let-7 miRNA levels and suppresses the retarded terminal differentiation of lateral hypodermal seam cells in mutants carrying the hypomorphic let-7(n2853) allele or lacking the let-7 family miRNA genes mir-48 and mir-241. Depletion of RACK-1 also increases the levels of precursor let-7 miRNA. When Dicer is knocked down and pre-miRNA processing is inhibited, depletion of RACK-1 still leads to increased levels of pre-let-7, suggesting that RACK-1 affects a biogenesis mechanism upstream of Dicer. No changes in the activity of the let-7 promoter or the levels of primary let-7 miRNA are associated with depletion of RACK-1, suggesting that RACK-1 affects let-7 miRNA biogenesis at the post-transcriptional level. Interestingly, rack-1 knockdown also increases the levels of a few other precursor miRNAs. Our results reveal that RACK-1 controls the biogenesis of a subset of miRNAs, including let-7, and in this way plays a role in the heterochronic gene pathway during C. elegans development.