Genhai Zhu

Low‐Density Lipoprotein Contributes to Endometrial Carcinoma Cell Proliferation, Migration, and Invasion by Activating the JAK–STAT Signaling Pathway

Background. Cholesterol‐rich low‐density lipoprotein (LDL) particles have been demonstrated to regulate breast cancer cell proliferation and migration, but their biological function and relevant mechanisms in endometrial carcinoma (EC) remain unclear Methods. Serum and tissue samples were collected from EC patients (n = 50) and patients with benign endometrial hyperplasia (n = 50). Ishikawa and RL95‐2 cells were stimulated with different concentrations of LDL, followed by treatment with a JAK2 inhibitor (SD‐1029). LDL concentrations were determined by ELISA. The in vitro biological behavior of cells was examined using the CCK‐8 assay, EdU staining, and Transwell assay. The tumorigenicity of LDL in vivo was examined using a xenograft mouse model. western blotting, immunofluorescence, and immunohistochemistry studies were performed to measure related protein expression. Results. The LDL concentrations and levels of p‐JAK2 and p‐STAT3 expression were elevated in the clinical samples. Similar trends in expression were detected in EC cells after LDL stimulation. LDL treatment significantly promoted EC cell proliferation, migration, and invasion, and also upregulated p‐JAK2 and p‐STAT3 expression in a dose‐dependent manner. Moreover, SD‐1029 dramatically blocked the LDL‐mediated effects on EC cells. Intravenous injection of LDLs promoted tumor growth in the xenograft nude mice, and also increased p‐JAK2, p‐STAT3, and Ki‐67 expression, and downregulated caspase‐3 expression. Conclusions. These findings indicate that LDLs exert an oncogenic effect in EC cells by activating the JAK/STAT signaling pathway, and also suggest the JAK/STAT pathway as a possible therapeutic target for EC.

Low‐density lipoprotein receptor‐related protein 5/6 promotes endometrial cancer progression and cancer cell immune escape

AbstractThe study investigated the potential association of the low‐density lipoprotein (LDL) genome with endometrial cancer progression based on the Gene Expression Omnibus data set and The Cancer Genome Atlas data set. Differential and weighted gene coexpression network analysis was performed on endometrial cancer transcriptome datasets GSE9750 and GSE106191. The protein‐protein interaction network was built using LDL‐receptor proteins and the top 50 tumor‐associated genes. Low‐density lipoprotein‐related receptors 5/6 (LRP5/6) in endometrial cancer tissues were correlated with oncogenes, cell cycle‐related genes, and immunological checkpoints using Spearman correlation. MethPrimer predicted the LRP5/6 promoter CpG island. LRP2, LRP6, LRP8, LRP12, low‐density lipoprotein receptor‐related protein‐associated protein, and LRP5 were major LDL‐receptor‐related genes associated with endometrial cancer. LRP5/6 was enriched in various cancer‐related pathways and may be a key LDL‐receptor‐related gene in cancer progression. LRP5/6 may be involved in the proliferation process of endometrial cancer cells by promoting the expression of cell cycle‐related genes. LRP5/6 may be involved in the proliferation of endometrial cancer cells by promoting the expression of cell cycle‐related genes. LRP5/6 may promote the immune escape of cancer cells by promoting the expression of immune checkpoints, promoting endometrial cancer progression. The MethPrimer database predicted that the LRP5/6 promoter region contained many CpG islands, suggesting that DNA methylation can occur in the LRP5/6 promoter region. LRP5/6 may aggravate endometrial cancer by activating the phosphoinositide 3‐kinase/protein kinase B pathway.

Tumor-associated macrophages promote cisplatin resistance in ovarian cancer cells by enhancing WTAP-mediated N6-methyladenosine RNA methylation via the CXCL16/CXCR6 axis

Abstract Purpose Tumor-promotive tumor-associated macrophages (TAMs) and the CXCL16/CXCR6 axis have been reported to be correlated with the limited efficacy of chemotherapy in ovarian cancer (OC). However, the role of TAM-secreted CXCL16 and the mechanism by which it affects the cisplatin (DDP) resistance of OC cells remain elusive. Methods We induced human THP-1 monocytes to differentiate into macrophages. Next, SKOV3 and TOV-112D cells were co-cultured with the macrophages, followed by incubation with increasing concentrations of DDP. The effects of CXCL16, CXCR6, and WTAP on the DDP resistance of OC cells were investigated using the CCK-8 assay, colony formation assay, flow cytometry, and TUNEL staining. CXCL16 concentrations were determined by ELISA. Quantitative real-time PCR and western blotting were used to examine related markers. Results Our results showed that after being co-cultured with TAMs, the DDP resistance of OC cells was significantly enhanced and their CXCL16 levels were elevated. Acquired DDP resistance was characterized by an increased IC50 value for DDP, the formation of cell colonies, and decreased levels of cell apoptosis, which were accompanied by reduced levels of caspase-3 and Bax expression, and increased levels of Bcl-2, PARP1, BRCA1, and BRCA2 expression. Either CXCL16 knockdown in TAMs or CXCR6 knockdown in OC cells suppressed the DDP resistance of OC cells that had been co-cultured with TAMs. Knockdown of CXCL16 affected m6A RNA methylation in OC cells, as reflected by decreased YTHDF1/WTAP expression and increased ALKBH5 expression. WTAP overexpression and knockdown promoted and suppressed the DDP resistance of OC cells, respectively. Conclusion Tumor-associated macrophages promote the cisplatin resistance of OC cells by enhancing WTAP-mediated N6-methyladenosine RNA methylation via the CXCL16/CXCR6 axis.