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' SIRPα transmitting 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-SIRPα in 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 tumors in vivo and 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.

Cervical cancer is the most common gynecological cancer in women worldwide. Human papillomavirus (HPV) is required but not sufficient for developing cervical cancer. HPV E6 and E7 proteins are able to directly interact with certain nuclear receptors; however, whether steroid hormone receptors mediate cervical carcinogenesis is not completely understood. The present study demonstrated via immunohistochemistry that estrogen receptor α (ERα) and androgen receptor (AR) expression were decreased in a sequential manner from healthy cervical tissues to cervical intraepithelial neoplasia tissues and further to cervical cancer (CC) tissues, whereas microRNA (miR)-130a-3p expression levels were higher in CC tissues compared with healthy tissues. Both ERα and AR were direct targets of miR-130a-3p, as determined by performing luciferase reporter assays and western blotting. Functionally, compared with the corresponding control groups, miR-130a-3p knockdown, ERα overexpression and AR overexpression significantly inhibited CC cell proliferation and invasion, as demonstrated by the results obtained from the Cell Counting Kit-8 and Transwell assays in vitro. In addition, antagomiR-130a decreased tumor size and weight in vivo compared with control antagomiR as determined via the xenograft tumor growth assay. Therefore, the results suggested that miR-130a-3p might contribute to tumor progression by suppressing ERα and AR, and serve as a promising candidate target for the treatment of patients with CC.

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. Methods: The interaction between nerve and EC cells were investigated by in vitro neural invasion assay and transwell coculture system. Then the nerve-related receptor gene glutamate ionotropic receptor AMPA type subunit 2 (GRIA2) was detected in EC tissues and cells using PCR array, western blotting, and immunohistochemistry. The role of GluR2 (gene name GRIA2) on EC proliferation, migration and invasion was evaluated by a GluR2 antagonist and shRNA. At the same time, the neurotransmitter effect on GluR2 (glutamate) from the cocultured conditional medium was measured using high-performance liquid chromatography (HPLC). Results: EC cell line Ishikawa (ISK) showed the ability to migrate along neurites in vitro and the numbers of migrated/invaded EC cells in the DRG neuron coculture group were significantly increased. The expression of GluR2 in EC tissue was found to be higher than that in para-carcinoma tissue. After GluR2 antagonist and GluR2 shRNA treatment, the proliferation, migration and invasion of ISK cells was markedly inhibited. Moreover, the ability of DRG neurons to promote the migration and invasion of ISK cells could also be attenuated by downregulation of GluR2, and the concentration of the neurotransmitter glutamate was notably increased in the coculture conditional medium compared to that in the DRG neuron or ISK cells alone. Conclusions: DRG neurons promote metastasis of EC cells via GluR2, which might be a risk factor for PNI in EC. Moreover, the perineural system may promote tumor invasion and metastasis under certain circumstances.

Oncogenic high‐risk human papillomavirus (HR‐HPV) infection causes a majority of cases of cervical cancer and pre‐cancerous cervical lesions. However, the mechanisms underlying the direct evolution from HPV‐16/18‐infected epithelium to cervical intraepithelial neoplasia (CIN) III, which can progress to cervical cancer, remain poorly identified. Here, we performed RNA‐seq after laser capture microdissection, and found that APOBEC3B was highly expressed in cervical cancer specimens compared with CIN III with HPV‐16/18 infection. Furthermore, immunohistochemical analysis confirmed that high levels of APOBEC3B were correlated with lymph node metastasis in cervical cancer. Subsequent experiments revealed that HPV‐16 E6 could upregulate APOBEC3B through direct binding to the promoter of APOBEC3B in cervical cancer cells. Silencing of APOBEC3B by stable short hairpin RNA‐mediated knockdown reduced the proliferative capacity of Caski and HeLa cells in vitro and in vivo, but had only a small effect on the migration and invasion of two cervical cancer cell lines. Finally, we identified the changes in gene expression following APOBEC3B silencing in Caski cells by microarray, demonstrating a biological link between APOBEC3B and CCND1 in cervical cancer cells. Importantly, through methyl‐capture sequencing and pyrosequencing, APOBEC3B was found to affect the levels of the downstream protein Cyclin D1 (which is encoded by the CCND1 gene) through hypomethylation of the CCND1 promoter. In conclusion, our study supports HPV‐16 E6‐induced APOBEC3B expression associates with proliferation of cervical cancer cells and hypomethylation of Cyclin D1. Thus, APOBEC3B may be a potential therapeutic target in human cervical cancer.

Herein, A non-invasive pathomics approach was developed to reveal the methylation status in patients with cervical squamous cell carcinoma and predict clinical outcomes and treatment response. Using the MethylMix algorithm, 14 methylation-driven genes were selected for further analysis. We confirmed that methylation-driven genes were differentially expressed in immune, stromal, and tumor cells. In addition, we constructed a methylation-driven model and explored the alterations in immunocyte infiltration between the different models. The methylation-driven subtypes identified in our investigation could effectively predict the clinical outcomes of cervical cancer. To further evaluate the level of methylation-driven patterns, we constructed a risk model with four genes. Significant correlations were observed between the score and immune response markers, including PD1 and CTLA4. Multiple immune infiltration algorithms evaluated the level of immunocyte infiltration between the high- and low-risk groups, while the components of anti-tumor immunocytes in the low-risk group were significantly increased. Subsequently, a total of 205 acquired whole-slide imaging (WSI) images were processed to capture image signatures, and the pathological algorithm was employed to construct an image prediction model based on the risk score classification. The model achieved an area under the curve (AUC) of 0.737 and 0.582 for the training and test datasets, respectively. Moreover, we conducted vitro assays for validation of hub risk gene. The proposed prediction model is a non-invasive method that combines pathomics features and genomic profiles and shows satisfactory performance in predicting patient survival and treatment response. More interdisciplinary fields combining medicine and electronics should be explored in the future.

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