Xiao Sun

Purpose: Progestin resistance is a critical obstacle for endometrial conservative therapy. Therefore, studies to acquire a more comprehensive understanding of the mechanisms are urgent. However, the pivotal molecules are still unexplored. Materials and Methods: We downloaded GSE121367 from the GEO database. The “limma” R language package was applied to identify differentially expressed genes (DEGs). We conducted Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA). Protein–protein interaction was constructed by STRING and visualized in Cytoscape. The tumor immune microenvironment was explored by the TISIDB database. Methylation validation and overall survival analysis were conducted by the TCGA database. In addition, the upstream modulators of hub genes were predicted by miRTarBase and Network Analyst databases. The expression levels of candidate genes were validated by quantitative real-time PCR (qRT-PCR), Western blot, and immunohistochemical assay (IHC). Cell growth, clone formation, migration, invasion, and wound healing assays were studied to explore the role of MSX1 in progestin resistance in vitro. Results: A total of 3,282 DEGs were identified and they were mostly enriched in the cell adhesion pathway. We screened out ten hub genes whose genomic alteration rates were low based on the current endometrial carcinoma sample sets. Has-miR-335-5p, has-miR-124-3p, MAZ, and TFDP1 were the most prominent upstream regulators. The methylation status of CDH1, JAG1, EPCAM, and MSX1 was decreased, corresponding to their high protein expression, which also predicted better overall survival. The homeobox protein of MSX1 showed significant tissue specificity and better prognostic value and its knockdown inhibited epithelial–mesenchymal transitions (EMT) and enhanced progesterone efficacy. Conclusion: Our study identified that the gene of MSX1 promised to be the specific indicator and therapeutic target for progestin resistance. This would shed new light on the underlying biological mechanism to overcome progestin resistance of endometrial cancer.

Perineural invasion (PNI) has guiding significances for nerve preservation in cervical cancer, but there is no definite marker indicating PNI. Two cervical cancer cell lines (HeLa and ME-180) showed significant abilities to migrate along neurites in vitro and in vivo. Morphological observation revealed that Schwann cells (SC) arrived at the sites of cervical cancer cells before the onset of cancer metastasis. We used high-throughput antibody array to screen the signals mediating the interaction of nerve cells and cancer cells and found the high expression of CCL2 in dorsal root ganglion (DRG). Meanwhile, serum CCL2 showed a notable raise especially in cervical adenocarcinoma. SC-derived CCL2 bound to its receptor CCR2 and promoted the proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) of cervical cancer cells. In turn, cancer cell-derived signals triggered the expression of metalloproteinases (MMPs) including MMP2, MMP9 and MMP12 in SCs, promoting SCs to dissolve matrix. These data demonstrated that the cancer-nerve crosstalk formed a tumor microenvironment (TME) that facilitated to PNI. We identified the CCL2/CCR2 axis as a potential marker to predict the PNI and affect the nerve preservation for cervical cancer.

Background: Perineural invasion (PNI) is correlated with negative prognosis in multiple cancers, but its role in endometrial cancer (EC) is still largely unknown; thus, targeted treatment for nerve infiltration is lacking as well.

Purpose: Perineural invasion (PNI) is the neoplastic invasion of nerves by cancer cells, a process that may prove to be another metastatic route besides direct invasion, lymphatic spread, and vascular dissemination. Given the increasing incidence and association with poor prognosis, revealing the pathogenesis of perineural invasion is of great importance. Materials and methods: Four datasets related to PNI were downloaded from the Gene Expression Omnibus database and used to construct weighted gene co-expression network analysis (WGCNA). The intersection of potential pathways obtained from further correlation and enrichment analyses of different datasets was validated by the coculture model of Schwann cells (SCs), flow cytometry and immunohistochemistry (IHC). Results: GSE7055 and GSE86544 datasets were brought into the analysis for there were some significant modules related to PNI, while GSE103479 and GSE102238 datasets were excluded for insignificant differences. In total, 13,841 genes from GSE86544 and 10,809 genes from GSE7055 were used for WGCNA. As a consequence, 19 and 26 modules were generated, respectively. The purple module of GSE86544 and the dark gray module of GSE7055 were positively correlated with perineural invasion. Further correlation and enrichment analyses of genes from the two modules suggested that these genes were mainly enriched in cell cycle processes; especially, the terms S/G2/M phase were enriched. Three kinds of cells grew vigorously after coculture with SCs ex vivo. The Ki67 staining of the cervical cancer samples revealed that the Ki67 index of cancer cells surrounding nerves was higher than of those distant ones. Conclusion: Our work has identified cancer cell proliferation as a common response to neural cancerous microenvironments, proving a foundation for cancer cell colonization and metastasis.

Endometrial cancer is one of the most common gynecological malignant tumors. The roles of competing endogenous RNAs (ceRNAs) in this disease, however, remain unclear. In this study, we constructed a ceRNA network to reveal the core ceRNAs in endometrial cancer. Differentially expressed genes were summarized from The Cancer Genome Atlas database, whereupon 140 genes were identified for building the network. Further correlation, survival, and enrichment analyses suggested that these genes may help towards elucidating the molecular mechanisms of endometrial cancer. After validation of the findings with the GSE17025 data set, LINC00958, microRNA‐761, and DOLPP1 were highlighted as the critical genes in the ceRNA network. Our work suggests that LINC00958 may regulate DOLPP1 by “sponging” miR‐761 in endometrial cancer.

There are rapidly emerging efforts to explore tumor-associated macrophages (TAMs) as a tumor therapy target. Tumor cells express CD47, which can interact with the macrophages’ SIRPαtransmitting a “don’t eat me” signal to macrophages. The expression of CD47 increases in various tumors to evade immune attack. However, the expression of CD47 in endometrial cancer (EC) and the role of CD47-SIRPαin the TAMs which mediate the progression of EC remain unclear. Our study shows that there are increased TAMs in EC which dominantly consist of M2 macrophages and contribute to the progression of EC. We confirm that CD47 is highly expressed in EC tissue using the TCGA database, qPCR, and flow cytometry. Instead of directly promoting the apoptosis of EC cells, anti-CD47 blocking antibody promoted phagocytosis of EC cells by macrophages and the increased phagocytosis ability was mediated by M2 macrophages in a coculture assay. Besides, CD47 blockade inhibited the growth of the EC tumorsin vivoand increased the infiltration of macrophages with antitumor ability in the tumor microenvironment (TME). These findings might assist in developing promising strategies that blocked the CD47-SIRPa interaction for EC therapy.

CCL20 mediates RANK/RANKL-induced epithelial-mesenchymal transition in endometrial cancer cells

Clinical prognostic significance and pro-metastatic activity of RANK/RANKL via the AKT pathway in endometrial cancer