Pathways and molecules for overcoming immunotolerance in metastatic gastrointestinal tumors.

Worldwide, gastrointestinal (GI) cancer is recognized as one of the leading malignancies diagnosed in both genders, with mortality largely attributed to metastatic dissemination. It has been identified that in GI cancer, a variety of signaling pathways and key molecules are modified, leading to the emergence of an immunotolerance phenotype. Such modifications are pivotal in the malignancy's evasion of immune detection. Thus, a thorough analysis of the pathways and molecules contributing to GI cancer's immunotolerance is vital for advancing our comprehension and propelling the creation of efficacious pharmacological treatments. In response to this necessity, our review illuminates a selection of groundbreaking cellular signaling pathways associated with immunotolerance in GI cancer, including the Phosphoinositide 3-kinases/Akt, Janus kinase/Signal Transducer and Activator of Transcription 3, Nuclear Factor kappa-light-chain-enhancer of activated B cells, Transforming Growth Factor-beta/Smad, Notch, Programmed Death-1/Programmed Death-Ligand 1, and Wingless and INT-1/beta-catenin-Interleukin 10. Additionally, we examine an array of pertinent molecules like Indoleamine-pyrrole 2,3-dioxygenase, Human Leukocyte Antigen G/E, Glycoprotein A Repetitions Predominant, Clever-1, Interferon regulatory factor 8/Osteopontin, T-cell immunoglobulin and mucin-domain containing-3, Carcinoembryonic antigen-related cell adhesion molecule 1, Cell division control protein 42 homolog, and caspases-1 and -12.

Noncoding RNAs-mediated overexpression of KIF14 is associated with tumor immune infiltration and unfavorable prognosis in lung adenocarcinoma.

Kinesin family member 14 (KIF14) is potentially oncogenic and acts as a chromokinesin via binding to microtubules and chromatin during the bipolar spindle formation. KIF14 overexpression is a significant prognostic biomarker in various cancers. However, the expression, prognosis, mechanism, and tumor immune regulation of KIF14 in lung adenocarcinoma (LUAD) remain obscure. Our results demonstrated that KIF14 was upregulated in a variety of cancers, including LUAD. High-expression of KIF14 in LUAD was associated with pathological tumor stage, N stage and unfavorable prognosis. Both univariate and multivariate Cox regression results demonstrated that KIF14 was a significant independent risk factor influencing the prognosis of LUAD patients. The most promising upstream ncRNA-associated pathway of KIF14 in LUAD was determined to be GSEC/TYMSOS-hsa-miR-101-3p axis according to the starBase and The Cancer Genome Atlas databases. Furthermore, upregulation of KIF14 in LUAD was positively correlated with tumor mutation burden, microsatellite instability, immune checkpoint-related gene expression, immune cell biomarkers, and tumor immune cell infiltration. This study reveals that ncRNAs-mediated overexpression of KIF14 is associated with tumor immune infiltration and unfavorable prognosis in LUAD.

Correction to: A novel role of glutathione S-transferase A3 in inhibiting hepatic stellate cell activation and rat hepatic fibrosis.

An amendment to this paper has been published and can be accessed via the original article.

A novel role of glutathione S-transferase A3 in inhibiting hepatic stellate cell activation and rat hepatic fibrosis.

BACKGROUND AND AIMS: Glutathione S-transferase A3 (GSTA3) is known as an antioxidative protease, however, the crucial role of GSTA3 in liver fibrosis remains unclear. As a recently we developed water-soluble pyridone agent with antifibrotic features, fluorofenidone (AKF-PD) can attenuate liver fibrosis, present studies were designed to explore the role of GSTA3 in liver fibrosis and its modulation by AKF-PD in vivo and in vitro. METHODS: Rats liver fibrosis models were induced by dimethylnitrosamine (DMN) or carbon tetrachloride (CCl4). The two activated hepatic stellate cells (HSCs) lines, rat CFSC-2G and human LX2 were treated with AKF-PD respectively. The lipid peroxidation byproduct malondialdehyde (MDA) in rat serum was determined by ELISA. The accumulation of reactive oxygen species (ROS) was measured by dichlorodihydrofluorescein fluorescence analysis. The expression of α-smooth muscle actin (α-SMA), fibronectin (FN), and phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2), p38 mitogen-activated protein kinase (p38 MAPK), c-Jun N-terminal kinase (JNK) and glycogen synthase kinase 3 beta (GSK-3ß) were detected by western blotting (WB). RESULTS: GSTA3 was substantially reduced in the experimental fibrotic livers and transdifferentiated HSCs. AKF-PD alleviated rat hepatic fibrosis and potently inhibited HSCs activation correlated with restoring GSTA3. Moreover, GSTA3 overexpression prevented HSCs activation and fibrogenesis, while GSTA3 knockdown enhanced HSCs activation and fibrogenesis resulted from increasing accumulation of ROS and subsequent amplified MAPK signaling and GSK-3ß phosphorylation. CONCLUSIONS: We demonstrated firstly that GSTA3 inhibited HSCs activation and liver fibrosis through suppression of the MAPK and GSK-3ß signaling pathways. GSTA3 may represent a promising target for potential therapeutic intervention in liver fibrotic diseases.