Endoplasmic Reticulum Membrane Protein Complex Regulates Cancer Stem Cells and is Associated with Sorafenib Resistance in Hepatocellular Carcinoma.

Background: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, underscoring the need for novel therapeutic targets. This study aimed to elucidate the role of endoplasmic reticulum membrane protein complex subunit 1 (EMC1) in HCC progression and its therapeutic potential. Methods: Publicly available sequencing data and biopsy specimens were analyzed to assess EMC's clinical value and functions in HCC. In vitro experiments validated EMC functions, and multiplex immunofluorescence analysis examined EMC-associated sorafenib resistance mechanisms. EMC1 expression was knocked down in HCC cell lines, followed by cell viability, wound healing, and transwell migration assays. Tumor growth and response to sorafenib treatment were evaluated in mouse models. Metabolomic analysis assessed changes in the TCA cycle. Results: EMC genes were aberrantly expressed in HCC, and high EMC1 expression correlated with poorer survival rates. EMC1 disruption enhanced HCC cells' sensitivity to sorafenib, reducing cell viability, increasing apoptosis, and decreasing tumor size and weight. EMC1 maintained cancer cell stemness and promoted M2 macrophage infiltration. Metabolomic analysis revealed significant changes in the TCA cycle, indicating EMC1's role in HCC metabolic reprogramming. Importantly, EMC1 is highly associated with sorafenib resistance, potentially linked to CTNNB1 mutation or activation. Conclusion: EMC1 plays a critical role in regulating the sorafenib resistance in HCC. Targeting EMC1 may improve HCC treatment efficacy.

LY6/PLAUR domain containing 3 (LYPD3) maintains melanoma cell stemness and mediates an immunosuppressive microenvironment.

BACKGROUND: Malignant melanoma is a highly heterogeneous skin cancer with the highest mortality rate among dermatological cancers. Catenins form functional networks in the nucleus to regulate gene expression and determine cell fate. Dysregulation of catenin expression correlates with the malignant characteristics of the tumor. We aimed to investigate the regulatory mechanisms of catenins in melanoma and to further define the function of catenin-related molecular signaling in the tumor microenvironment. METHODS: In this study, a bioinformatics approach combined with experimental validation was used to explore the potential tumor biology mechanisms of catenin-related signaling. RESULTS: Melanoma patients can be divided into two catenin clusters. Patients defined by high Junction Plakoglobin (JUP), Plakophilin 1 (PKP1), Plakophilin 3 (PKP3) levels (C2) had shorter survival time than other patients (C1). We demonstrated that JUP regulates Anterior Gradient 2 (AGR2)/LY6/PLAUR Domain Containing 3 (LYPD3) to maintain melanoma stemness and promotes glycolysis. We also found that LYPD3 was co-expressed with S100A9 and associated with immunosuppressive tumor microenvironment (TME). CONCLUSION: The JUP/AGR2/LYPD3 signaling axis plays an important role in the malignant features of melanoma. Targeting the JUP/AGR2/LYPD3 signaling axis can help develop promising drugs.

An Analysis Regarding the Association Between the Nuclear Pore Complex (NPC) and Hepatocellular Carcinoma (HCC).

Background: The nuclear pore complex (NPC) is the main mediator of nuclear and cytoplasmic communication, and delaying or blocking nuclear RNA export and protein shuttling can inhibit cell proliferation and induce apoptosis. Although NPC is a research hotspot in structural biology, relevant studies in hepatocellular carcinoma are scarce, especially in terms of translation into clinical practice. Methods: This study used a bioinformatics approach combining validation experiments to investigate the biological mechanisms that may be related with NPC. A series of experiments performed to explore the function of the Targeting protein for Xenopus kinesin-like protein 2 (TPX2) in HCC. Results: Patients with HCC can be divided into two NPC clusters. Patients with high NPC levels (C1) had a shorter survival time than those with low NPC levels (C2) and are characterised by high levels of proliferative signals. We demonstrated that TPX2 regulates HCC growth and inhibits apoptosis in an NPC-dependent manner and contributes to the maintenance of HCC stemness. We developed the NPCScore to predict the prognosis and degree of differentiation in HCC patients. Conclusion: NPC plays an important role in the malignant proliferation of HCC. Assessing NPC expression patterns could help enhance our understanding of tumor cell proliferation and could guide more effective chemotherapeutic strategies.

Prognostic Value of LHFPL Tetraspan Subfamily Member 6 (LHFPL6) in Gastric Cancer: A Study Based on Bioinformatics Analysis and Experimental Validation.

PURPOSE: The identification of biomarkers and effective therapeutic targets for gastric cancer (GC), the most common cause of cancer-related deaths around the world, is currently a major focus in research. Here, we examined the utility of LHFPL6 as a prognostic biomarker and therapeutic target for GC. METHODS: We explored the clinical relevance, function, and molecular role of LHFPL6 in GC using the MethSurv, cBioPortal, TIMER, Gene Expression Profiling Interactive Analysis, ONCOMINE, MEXPRESS, and EWAS Atlas databases. The GSE118919, GSE29272, and GSE13861 datasets were used for differential expression analysis. Using The Cancer Genome Atlas, we developed a Cox regression model and assessed the clinical significance of LHFPLs. In addition, we used the "CIBERSORT" algorithm to make reliable immune infiltration estimations. Western blot and immunohistochemistry were used to examine protein expression. Cell migration and invasion were assessed using transwell experiments. THP-1-derived macrophages and GC cells were co-cultured in order to model tumor-macrophage interactions in vitro. The levels of CD206 and CD163 were measured using immunofluorescence assays. The results were visualized with the "ggplot2" and "circlize" packages. RESULTS: Our results showed that in GC, LHFPL6 overexpression was significantly associated with a poor prognosis. Our findings also suggested that LHFPL6 may be involved in the activation of the epithelial-mesenchymal transition. Furthermore, LHFPL6 expression showed a positive correlation with the abundance of M2 macrophages, which are potent immunosuppressors. CONCLUSION: LHFPL6 could be a prognostic biomarker and therapeutic target for GC.

Overexpression of NREP Promotes Migration and Invasion in Gastric Cancer Through Facilitating Epithelial-Mesenchymal Transition.

The identification of biomarkers and effective therapeutic targets for gastric cancer (GC), the most common cause of cancer-related deaths around the world, is currently a major focus area in research. Here, we examined the utility of Neuronal Regeneration Related Protein (NREP) as a prognostic biomarker and therapeutic target for GC. We assessed the clinical relevance, function, and molecular role of NREP in GC using bioinformatics analysis and experimental validation. Our results showed that in GC, NREP overexpression was significantly associated with a poor prognosis. Our findings also suggested that NREP may be involved in the activation of cancer-associated fibroblasts and the epithelial-mesenchymal transition (EMT), with transforming growth factor ß1 mediating both processes. In addition, NREP expression showed a positive correlation with the abundance of M2 macrophages, which are potent immunosuppressors. Together, these results indicate that NREP is overexpressed in GC and affects GC prognosis. Thus, NREP could be a prognostic biomarker and therapeutic target for GC.