This study investigated the effects of estrogen and estrogen receptor alpha (ERα) on the pathogenesis of primary biliary cholangitis (PBC) in human intrahepatic bile duct epithelial cells (HiBECs). The researchers measured serum levels of ERα, oxidative stress indicators, and cytokines in PBC patients and healthy controls. They examined the expression of ERα, pyruvate dehydrogenase complex E2-component (PDC-E2), and apoptosis-related proteins in the small bile ducts. In vitro experiments with HiBECs showed that estrogen had a dual effect on cell viability, increasing it at low concentrations but reducing it at higher concentrations. ERα activation led to mitochondrial damage, apoptosis, and upregulation of ERα and PDC-E2 expression. These findings suggest that the high expression of ERα in the bile ducts contributes to mitochondrial damage, inflammation, and apoptosis in PBC. The study highlights ERα as a potential target for understanding and treating estrogen-mediated PBC pathogenesis.

Natural killer (NK) cells are the critical elements of the innate immune response and implicated in rapidly recognizing and eliminating cancer cells. However, the tumor-suppressive ability of NK cells is often impaired in several cancer types. The critical roles of microRNAs have been elucidated by increasing evidences, while the regulation of miR-338-3p in anti-tumor activation of NK cells and its relationship with estrogen in breast cancer (BC) are still confusing. Here, miR-338-3p level was found to be significantly downregulated in BC tissues and estrogen receptor positive (ER+ ) cells, this difference was more obvious in ER+ patients or BC patients at advanced stage (TNM III and IV). MiR-338-3p level was shown to be downregulated by 17β-estradiol in BC cells (MDA-MB-231 cells and MCF-7) in vitro. MiR-338-3p overexpression decreased disintegrin and metalloprotease-17 (ADAM17) secretion in MDA-MB-231 (ER- ) and MCF-7 (ER+ ) cells. In addition, miR-338-3p overexpression or treatment with anti-ADAM17 antibody could down-regulate granzyme B, CD16, and NKG2D in NK cells, which was reversed by human recombinant ADAM17. Furthermore, these educated NK cells could promote the viability of MDA-MB-231 or MCF-7 cells. Taken together, our results demonstrate that miR-338-3p was negatively regulated by estrogen in BC cells, impairing NK cell's activity by the up-regulation of ADAM17, and conversely promoted the viability of BC cells. Therefore, the estrogen/miR-338-3p/ADAM17 axis is critically implicated in BC pathogenesis and may provide potential targets for BC diagnosis and treatment.

With high morbidity and mortality, hepatocellular carcinoma (HCC) deserves further exploration in its pathogenesis mechanisms for promising prognostic and therapeutic markers. This research was conducted to dig out roles of exosomal ZFPM2-AS1 in HCC.

The level of exosomal ZFPM2-AS1 in HCC tissue and cells was determined by Real-time fluorescence quantitative PCR. Pull-down assay and dual-luciferase reporter assay were performed to identify interactions between ZFPM2-AS1 and miRNA-18b-5p, as well as miRNA-18b-5p and PKM. Western blotting was employed to explore the potential regulatory mechanism. Several in vitro assays were conducted in mice xenograft and orthotopic transplantation models to investigate impacts of exosomal ZFPM2-AS1 on HCC development, metastasis, and macrophage infiltration.

ZFPM2-AS1 was activated in HCC tissue and cells, with high enrichment in HCC-derived exosomes. Exosomal ZFPM2-AS1 enhances the cell abilities and stemness of HCC. MiRNA-18b-5p was directly targeted by ZFPM2-AS1 which triggered PKM expression via sponging miR-18b-5p. Exosomal ZFPM2-AS1 modulated glycolysis via PKM in an HIF-1α dependent way in HCC, promoting M2 polarization, and macrophage recruitment. Furthermore, exosomal ZFPM2-AS1 enhanced HCC cell growth, metastasis, and M2 infiltration in vivo.

Exosomal ZFPM2-AS1 exerted regulatory function on the progression of HCC via miR-18b-5p/PKM axis. ZFPM2-AS1 could be promising biomarker for the diagnosis and therapies of HCC.

New drugs are urgently needed for the treatment of liver cancer, a feat that could be feasibly accomplished by finding new therapeutic purposes for marketed drugs to save time and costs. As a new class of national anti-infective drugs, carrimycin (CAM) has strong activity against gram-positive bacteria and no cross resistance with similar drugs. Studies have shown that the components of CAM have anticancer effects.

To obtain a deeper understanding of CAM, its distribution, metabolism and anti-inflammatory effects were assessed in the organs of mice, and its mechanism of action against liver cancer was predicted by a network pharmacology method.

In this paper, the content of isovaleryl spiramycin III was used as an index to assess the distribution and metabolism of CAM and its effect on inflammatory factors in various mouse tissues and organs. Reverse molecular docking technology was utilized to determine the target of CAM, identify each target protein based on disease type, and establish a target protein-disease type network to ascertain the effect of CAM in liver cancer. Then, the key action targets of CAM in liver cancer were screened by a network pharmacology method, and the core targets were verified by molecular docking and visual analyses.

The maximum CAM concentration was reached in the liver, kidney, lung and spleen 2.5 h after intragastric administration. In the intestine, the maximum drug concentration was reached 0.5 h after administration. In addition, CAM significantly reduced the interleukin-4 (IL-4) levels in the lung and kidney and especially the liver and spleen; moreover, CAM significantly reduced the IL-1β levels in the spleen, liver, and kidney and particularly the small intestine and lung. CAM is predicted to regulate related pathways by acting on many targets, such as albumin, estrogen receptor 1, epidermal growth factor receptor and caspase 3, to treat cancer, inflammation and other diseases.

We determined that CAM inhibited inflammation. We also predicted the complex multitargeted effects of CAM that involve multiple pathways and the diversity of these effects in the treatment of liver cancer, which provides a basis and direction for further clinical research.

Glioblastoma (GBM) is the most common central nervous system tumor and is associated with poor outcomes. There have been no significant improvements in GBM mortality in recent decades. ER-α36 is a variant of ER-α66 that may be involved in carcinoma growth and proliferation via genomic and nongenomic mechanisms. This variant might play an essential role in tamoxifen resistance of several tumors. Previously, our laboratory found that ER-α36 is expressed in GBM and participates in proliferation; nevertheless, the role of ER-α36 in GBM invasion remains unknown. This study aimed to determine the effects of the ER-α36 modulator SNG162 on GBM growth and invasion. U251 cells, U87cells, and U87-36KD cells with knockdown of ER-α36 expression were cultured under the two-dimensional and the three-dimensional (3D) environments. GBM cells growth was examined by cell counting, flow cytometry, western blot, and MTT assays. Invasiveness was measured using confocal microscopy in the 3D environment. Growth of U87 cells with downregulated EGFR and ER-α36 expression was significantly reduced after treatment with 1 µM, 3 µM, and 5 µM of SNG162; growth inhibition in U251 cells was more potent than in U87 cells, although the expression level of ER-α36 in U251 cells was lower than in U87 cells. We found that 1 μM SNG162 suppressed E₂-induced MAPK/ERK pathway activation in U87 cells. We also showed that SNG162 inhibited U87 cells invasion; however, it did not significantly affect U251 and U87-36KD cells invasion using the 3D culture method. Finally, we determined that ER-α36 was expressed in the nucleus of invading GBM cells, and SNG162 significantly inhibited the expression of ER-α36 in these cells. SNG162 inhibited the expression of EGFR on cell membranes of non-invasive GBM cells. These results suggest that SNG162 could be a therapeutic agent for GBM by targeting ER-α36.

Human discs large-associated protein 5 (DLGAP5), a microtubule-associated protein, has been reported to be upregulated in several tumors. However, the role of DLGAP5 in endometrial cancer (EC) progression and the related underlying mechanism were still unknown. A bioinformatics analysis was performed to analyze the expression and prognostic significance of DLGAP5 in EC tissues using TCGA, CPTAC, Human Protein Atlas, and GSE63678 databases, UALCAN web tool, and the Kaplan-Meier plotter. Effects of DLGAP on EC cell malignant properties were evaluated by CCK-8, flow cytometry analysis, TUNEL assay, caspase-3 activity assay, and Transwell invasion assay. The expression of DLGAP5, Wnt3, c-Myc, Ki67, and cleaved caspase-3 was detected by western blot analysis. DLGAP5 was highly expressed and correlated with poor prognosis in EC patients. DLGAP5 knockdown inhibited proliferation and invasion, triggered apoptosis, and increased caspase-3 activity in EC cells. Additionally, DLGAP5 knockdown inactivated the Wnt/β-catenin signaling pathway in EC cells. Moreover, β-catenin overexpression abolished the effects of DLGAP5 knockdown on the malignant phenotypes of EC cells. DLGAP5 silencing suppressed the malignant properties in EC cells by inactivating the Wnt/β-catenin pathway.

Preclinical tumor models with native tissue microenvironments provide essential tools to understand how heterogeneous tumor phenotypes relate to drug response. Here we present syngeneic graft models of aggressive, metastasis-prone histopathology-specific NSCLC tumor types driven by KRAS mutation and loss of LKB1 (KL): adenosquamous carcinoma (ASC) and adenocarcinoma (AC). We show that subcutaneous injection of primary KL; ASC cells results in squamous cell carcinoma (SCC) tumors with high levels of stromal infiltrates, lacking the source heterogeneous histotype. Despite forming subcutaneous tumors, intravenously injected KL;AC cells were unable to form lung tumors. In contrast, intravenous injection of KL;ASC cells leads to their lung re-colonization and lesions recapitulating the mixed AC and SCC histopathology, tumor immune suppressive microenvironment and oncogenic signaling profile of source tumors, demonstrating histopathology-selective phenotypic dominance over genetic drivers. Pan-ERBB inhibition increased survival, while selective ERBB1/EGFR inhibition did not, suggesting a role of the ERBB network crosstalk in resistance to ERBB1/EGFR. This immunocompetent NSCLC lung colonization model hence phenocopies key properties of the metastasis-prone ASC histopathology, and serves as a preclinical model to dissect therapy responses and metastasis-associated processes.