Immunoglobulin superfamily 6 is a molecule involved in the anti-tumor activity of macrophages in lung adenocarcinoma.

BACKGROUND: Immunoglobulin superfamily 6 (IGSF6) is a novel member of the immunoglobulin superfamily and has been implicated in various diseases. However, the specific role of IGSF6 in the anti-tumor immunity within lung adenocarcinoma (LUAD) remains unclear. METHODS: We analyzed the IGSF6 expression in LUAD using data from TCGA, and we performed qRT-PCR and western blotting to validate these findings using tissue samples obtained from LUAD patients. Images of IHC staining were obtained from HPA. To assess the clinical relevance of IGSF6 expression, we utilized UALCAN and SPSS to analyze its association with major clinical features of LUAD. Additionally, we employed ROC curves and survival analysis to evaluate the potential diagnostic and prognostic value of IGSF6 in LUAD. To gain insights into the functional implications of IGSF6, we performed enrichment analysis using the R software clusterProfiler package. Moreover, we utilized TIMER2.0 and TISIDB to investigate the relationship between IGSF6 and immune infiltrates in LUAD. The proportion of tumor-infiltrating immune cells in LUAD was assessed using FCM, and their correlation with IGSF6 expression in tumor tissues was analyzed. The localization of IGSF6 protein on macrophages was confirmed using the HPA and FCM. To determine the regulatory role of IGSF6 on macrophage activity in LUAD, we employed ELISA, FCM, and tumor-bearing models. RESULTS: We discovered that both IGSF6 mRNA and protein levels were significantly decreased in LUAD. Additionally, we observed a negative correlation between IGSF6 expression and TNM stages as well as pathologic stages in LUAD. Notably, IGSF6 exhibited high sensitivity and specificity in diagnosing LUAD, and was positively associated with the survival rate of LUAD patients. Furthermore, IGSF6 expression was closely linked to gene sets involved in immune response. IGSF6 expression showed a positive correlation with immune infiltrates exhibiting anti-tumor activity, particularly M1 macrophages. We confirmed the predominant localization of the IGSF6 protein on the membrane of M1 macrophages. Importantly, the knockdown of IGSF6 resulted in a reduction in the anti-tumor activity of M1 macrophages, thereby promoting tumor progression. CONCLUSION: IGSF6 is a molecule that is essential for the anti-tumor activity of macrophages in LUAD.

Characterization of the Estrogen Response Helps to Predict Prognosis and Identify Potential Therapeutic Targets in Cholangiocarcinoma.

Cholangiocarcinoma (CCA) is an aggressive malignancy originating from the epithelium of the bile duct. The prognosis of patients is poor regardless of radical resection and chemoradiotherapy. The current classification and prognostic model of CCA are unable to satisfy the requirements for predicting the clinical outcome and exploring therapeutic targets. Estrogen signaling is involved in diverse cancer types, and it has long been established that CCA could be regulated by estrogen. In our study, estrogen response was identified to be significantly and stably correlated with poor prognosis in CCA. Employing several algorithms, CCA was classified into ES cluster A and B. ES cluster B was mainly composed of patients with fluke infection and overlapped with CCA cluster 1/2, and ES cluster A was mainly composed of patients without fluke infection and overlapped with CCA cluster 3/4. COMT and HSD17B1 were identified to be responsible for the differential estrogen response between ES clusters A and B, and the estrogen response may be correlated with the differentiation and cancer stemness of CCA at the single-cell level. Complement activation and the expression of C3 and C5, which are mainly expressed by CCA cells, were significantly downregulated in ES cluster B. An estrogen response risk score (ESRS) model was constructed to predict the prognosis of CCA, followed by a nomogram integrating ESRS and clinical features. Finally, altered pathways, applicable drugs and sensitivity to chemical drugs were analyzed specific to the estrogen response. In summary, our results provide insights into the role of the estrogen response in CCA progression as well as applicable drugs and potential therapeutic targets in estrogen metabolism, the complement system and ESRS-related pathways.

Hesperadin suppresses pancreatic cancer through ATF4/GADD45A axis at nanomolar concentrations.

Pancreatic cancer (PC) is a fatal disease with poor survival and limited therapeutic strategies. In this study, we identified Hesperadin as a potent anti-cancer compound against PC, from a high-throughput screening of a commercial chemical library associated with cell death. Hesperadin induced potent growth inhibition in PC cell lines and patient-derived tumor organoids in a dose- and time-dependent manner, with IC50 values in the nanomolar range. Cellular studies showed that Hesperadin caused mitochondria damage in PC cells, resulting in reactive oxygen species production, ER stress and apoptotic cell death. Transcriptomic analysis using RNA-sequencing data identified GADD45A as a potential target of Hesperadin. Mechanistic studies showed that Hesperadin could increase GADD45A expression in PC cells via ATF4, leading to apoptosis. Moreover, immunohistochemical staining of 92 PC patient samples demonstrated the correlation between ATF4 and GADD45A expression. PC xenograft studies demonstrated that Hesperadin could effectively inhibit the growth of PC cells in vivo. Together, these findings suggest that Hesperadin is a novel drug candidate for PC.

Circulating CD15+ LOX-1+ PMN-MDSCs are a potential biomarker for the early diagnosis of non-small-cell lung cancer.

AIMS: Non-small-cell lung cancer (NSCLC) is the most common clinical lung cancer. Polymorphonuclear-myeloid derived suppressor cells (PMN-MDSCs), which are the major population of MDSCs, are involved in NSCLC progression. Recently, it was found that lectin-type oxidized LDL receptor 1 (LOX-1) could identify human PMN-MDSCs. However, the role of CD15+ LOX-1+ PMN-MDSCs in NSCLC early diagnosis has not been revealed. Here, we tried to confirm the application of the newly identified CD15+ LOX-1+ PMN-MDSCs in the early diagnosis of NSCLC. METHODS: Flow cytometry (FCM) was used to detect the proportion of CD15+ LOX-1+ PMN-MDSCs in the peripheral blood (PB) of healthy controls (HC) and NSCLC patients. The correlation of CD15+ LOX-1+ PMN-MDSC frequency with levels of cytokeratin 19-fragments (CYFRA21-1), carcinoembryonic antigen (CEA), and carbohydrate antigen 125 (CA125) was analysed. Receiver operating characteristic (ROC) curve was used to estimate the diagnostic efficacy of CD15+ LOX-1+ PMN-MDSCs for NSCLC. Additionally, the association of CD15+ LOX-1+ PMN-MDSC frequency with NSCLC prognosis/recurrence after surgery was explored. RESULTS: The proportion of CD15+ LOX-1+ PMN-MDSCs increased in PB of NSCLC patients. CD15+ LOX-1+ PMN-MDSC proportion was positively correlated with levels of CEA, CA125 and CYFRA21-1. Detection of PMN-MDSC percentage in PB owed high sensitivity and specificity for NSCLC diagnosis. The proportion of CD15+ LOX-1+ PMN-MDSCs decreased in patients after surgery. The frequency of CD15+ LOX-1+ PMN-MDSCs was lower in NSCLC patients without recurrence compared to those with recurrence after surgery. CONCLUSIONS: Circulating CD15+ LOX-1+ PMN-MDSCs are a potential diagnostic marker for NSCLC, and are associated with NSCLC prognosis and recurrence after surgery.