Pan-Cancer Analysis of the Prognostic and Immunotherapeutic Value of MITD1.

Microtubule-interacting and trafficking domain containing 1 (MITD1) is associated with abscission during cytokinesis. However, systematic investigation into its role in cancer is lacking. Therefore, we explored the pan-cancer role of MITD1 using multiple databases. Expression and clinical survival, immunological, and enrichment analyses were performed using R packages and online tools. For breast cancer, single-cell level analysis, immunochemistry, and in vitro experiments were performed to explore the mechanism of MITD1. A nomogram was established to predict the prognosis of patients with breast cancer and evaluate the immunotherapy biomarker based on two datasets. In some cancers, high MITD1 expression was associated with a more favorable prognosis. For instance, it inhibited tumor cell proliferation and migration in breast cancer. MITD1 may regulate cancer development by altering the tumor microenvironment, and MITD1 expression may predict the response to immune checkpoint blockade, platinum, and poly ADP-ribose polymerase inhibitor therapies. Our nomogram was used to determine the prognosis of patients with breast cancer. MITD1 can also predict the response to immunotherapy. Our first pan-cancer study of MITD1 has shown that it plays different roles in cancer development and therapy. In breast cancer, MITD1 inhibited cell proliferation and migration and serves as a new biomarker.

Fibroblast activation protein-alpha knockdown suppresses prostate cancer cell invasion and proliferation.

BACKGROUND: Prostate cancer is one of the most common malignant tumors of the male genitourinary system. Fibroblast activation protein alpha (FAP-α) overexpression has been shown to occur in a wide range of tumors. However, the specific mechanism of FAP-α in the development of prostate cancer has not been reported. METHODS: In this study, real-time quantitative PCR (qRT-PCR) was used to detect the relative expression of FAP-α mRNA in prostate cancer cell lines (PC-3, LNCaP, and DU145) and human normal prostate epithelial cell line RWPE-1. Small interfering RNA (siRNA) targeting FAP-α and vectors expressing exogenous FAP-α were transfected to prostate cancer cells (LNCaP and DU145) to investigate the function of FAP-α. BALB/c nude mice were injected with DU145 cells which were transfected with NC-siRNA, FAP-α-siRNA-1, or FAP-α-siRNA-2. RESULTS: Compared to adjacent normal tissues, FAP-α protein and mRNA levels in prostate cancer tissues increased significantly (P<0.05). Compared to patients with high FAP-α mRNA levels, patients with low FAP-α mRNA levels had a significantly higher survival rate (χ²=5.050, log-rank P=0.025). Overexpression of FAP-α in LNCaP cells markedly inhibited cell apoptosis, and promoted cell invasion and proliferation. In contrast, knockdown of FAP-α expression in DU145 cells can significantly reduce invasion, proliferation, and promote apoptosis in prostate cancer. Immunofluorescence assay further indicated that down-regulation of FAP-α could suppress the nuclear translocation of ß-catenin. An in vivo study found that compared with the NC-siRNA group, the tumor weight and tumor volume in the FAP-α-siRNA-1 and FAP-α-siRNA-2 groups were significantly decreased. CONCLUSIONS: In conclusion, down-regulation of FAP-α can inhibit the invasion and proliferation of prostate cancer. Our study provides a theoretical basis for the targeted treatment of prostate cancer.

Key sunitinib-related biomarkers for renal cell carcinoma.

BACKGROUND: Renal cell carcinoma (RCC) contributed to 403,262 new cases worldwide in 2018, which constitutes 2.2% of global cancer, nevertheless, sunitinib, one of the major targeted therapeutic agent for RCC, often developed invalid due to resistance. Emerging evidences suggested sunitinib can impact tumor environment which has been proven to be a vital factor for tumor progression. METHODS: In the present study, we used ssGSEA to extract the immune infiltrating abundance of clear cell RCC (ccRCC) and normal control samples from GSE65615, TCGA, and GTEx; key immune cells were determined by Student's t-test and univariable Cox analysis. Co-expression network combined with differentially expressed analysis was then applied to derive key immune-related genes for ccRCC, followed by the identification of hub genes using differential expression analysis. Subsequently, explorations and validations of the biological function and the immune-related and sunitinib-related characteristics were conducted in KEGG, TISIDB, Oncomine, ICGC, and GEO databases. RESULTS: We refined immature dendritic cells and central memory CD4 T cells which showed associations with sunitinib and ccRCC. Following, five hub genes (CRYBB1, RIMBP3C, CEACAM4, HAMP, and LYL1) were identified for their strong relationships with sunitinib and immune infiltration in ccRCC. Further validations in external data refined CRYBB1, CEACAM4, and HAMP which play a vital role in sunitinib resistance, immune infiltrations in ccRCC, and the development and progression of ccRCC. In conclusion, our findings could shed light on the resistance of sunitinib in ccRCC and provide novel biomarkers or drug targets for ccRCC.

A prognostic nomogram based on competing endogenous RNA network for clear-cell renal cell carcinoma.

BACKGROUND: Clear-cell renal cell carcinoma (ccRCC) is stubborn to traditional chemotherapy and radiation treatment, which makes its clinical management a major challenge. Recently, we have made efforts in understanding the etiology of ccRCC. Increasing evidence revealed that the competing endogenous RNA (ceRNA) was involved in the development of varied tumors. However, a comprehensive analysis of the prognostic model based on lncRNA-miRNA-mRNA ceRNA regulatory network of ccRCC with large-scale sample size and RNA-sequencing expression data is still limited. METHODS: RNA-sequencing expression data were taken out from GTEx database and TCGA database, a total of 354 samples with ccRCC and 157 normal controlled samples were included in our study. The ccRCC-specific genes were obtained by WGCNA and differential expression analysis. Following, the communication of mRNAs and lncRNAs with targeted miRNAs were predicted by MiRcode, starBase, miRTarBase, and TargetScan. A gene signature of eight genes was further constructed by univariate Cox regression, Lasso methods, and multivariate Cox regression analysis. RESULTS: A total of 2191 mRNAs and 1377 lncRNAs was identified, and a dysregulated ceRNA network for ccRCC was established using 7 mRNAs, 363 lncRNAs, and 3 miRNAs. Further, a gene signature including eight genes based on this ceRNA was determined followed by the development of a nomogram predicting 1-, 3-, and 5-year survival probability for ccRCC. CONCLUSION: It could contribute to a better understanding of ccRCC tumorigenesis mechanism and guide clinicians to make a more accurate treatment decision.

LncRNA OIP5-AS1 inhibits ferroptosis in prostate cancer with long-term cadmium exposure through miR-128-3p/SLC7A11 signaling.

Previous studies suggest that cadmium (Cd) is one of the causative factors of prostate cancer (PCa), but the effect of chronic Cd exposure on PCa progression remains unclear. Besides, whether long noncoding RNAs (lncRNAs) are involved in the regulation of prolonged exposure to Cd in PCa needs to be elucidated. In the present study, we found that the serum concentration of Cd in PCa patients was positively correlated with the Gleason score and tumor-node-metastasis (TNM) classification. To simulate chronic Cd exposure in PCa, we subjected PC3 and DU145 cells to long-term, low-dose Cd exposure and further examined tumor behavior. Functional studies identified that chronic Cd exposure promoted cell growth and ferroptosis resistance in vitro and in vivo. Furthermore, we found that lncRNA OIP5-AS1 expression was greatly elevated in PC3 and DU145 cells upon chronic Cd exposure. Dysregulation of OIP5-AS1 expression mediated cell growth and Cd-induced ferroptosis. Mechanistically, we demonstrated that OIP5-AS1 served as an endogenous sponge of miR-128-3p to regulate the expression of SLC7A11, a surrogate marker of ferroptosis. Moreover, miR-128-3p decreased cell viability by enhancing ferroptosis. Taken together, our data indicate that lncRNA OIP5-AS1 promotes PCa progression and ferroptosis resistance through miR-128-3p/SLC7A11 signaling.

Identification of docetaxel-related biomarkers for prostate cancer.

Prostate cancer (PCa) which was the second commonly diagnosed malignancy, contributed to the top fifth carcinoma death in men. Nevertheless, the main chemotherapeutic agent docetaxel came to failure due to chemoresistance. Recently, increasing evidence suggested the importance of tumour microenvironment (TME) in PCa. The present study aimed to explore the specific TME in PCa and find biomarkers related to both immune infiltration and docetaxel. The docetaxel-specific genes and differential expression genes comparing PCa with normal control samples were derived using DESeq2 and zinbwave with GSE140440, TCGA and GTEx datasets. Immune-infiltration-related genes were identified using CIBERSORT and co-expression network analysis. Key genes related to both docetaxel and immune infiltrating in PCa, including nine genes, namely ZNF486, IFI6, TMOD2, HSPA4L, ITPR1, LRRC37A7P, APOC1, APOBEC3G, and ITGA2, were determined by overlapping above three gene sets. ITGA2 was then defined as the hub gene for its significant prognostic implications. Further validations conducted on Oncomine, GEO, TISIDB, MSigDB, and The Human Protein Atlas confirmed the docetaxel-specific and immune infiltrating characteristics of ITGA2. To sum up, our findings could provide a better understanding of immune infiltrating and docetaxel-resistance in PCa, mostly, ITGA2 could serve as potential prognosis biomarkers and targets for the combination of docetaxel.

A comprehensive characterization of the transcriptome in enzalutamide resistance prostate cancer.

BACKGROUND: Prostate cancer (PCa) contributes to more than 1.2 million newly diagnosed cases and more than 350,000 deaths each year, making it the second most common malignancy and the fifth leading cause of cancer-related deaths in men worldwide. Treatment of PCa is further complicated by drug resistance to enzalutamide. The present study comprehensively details the genomic characteristics of enzalutamide-resistant PCa. METHODS: The determination of enzalutamide-related genes in GSE163240 and GSE136129 was conducted by differential expression analysis, gene set enrichment analysis (GSEA) suggested that these genes were highly correlated with immune-related pathways. Subsequently, network analysis including module analysis and degree analysis and univariable cox analysis were conducted, which led to the identification of both hub genes [contactin 2 (CNTN2) and frizzled class receptor 2 (FZD2)]. RESULTS: GSEA suggested that these genes were highly correlated with immune-related pathways. Subsequently, network analysis, including module analysis and degree analysis, and univariable Cox analysis resulted in the identification of two hub genes, CNTN2 and FZD2, which were further validated using the Gene Expression Omnibus (GEO) and Molecular Signatures Database (MSigDB). GSEA and CIBERSORT indicated that both hub genes were highly correlated with immune-related functions in PCa. CONCLUSIONS: In conclusion, this study comprehensively described the transcriptome landscape of enzalutamide-resistant PCa and identified two hub genes, CNTN2 and FZD2, that play an important role in enzalutamide-mediated immune infiltration in PCa.

Benefits from standalone durvalumab treatment in an elderly patient with advanced prostatic sarcoma: a case report.

There is a lacking of effective therapeutic strategies in the treatment of advanced prostatic sarcoma with high-frequency microsatellite instability (MSI-H) or mismatch repair deficient (dMMR). In this study, we present the first described a case of advanced MSI-H and dMMR prostatic sarcoma in elderly patients with multiple comorbidities, who received an anti-PD-L1 monoclonal antibody (durvalumab) as the first-line treatment and achieved partial remission (PR) without visible adverse events. A 91-year-old male patient presented with frequent urination and defecation difficulty for over three months, aggravating for ten days. Digital rectal examination showed the prostate gland was III° enlargement and tough with a smooth surface. The MRI showed occupying lesions in the prostate without distant metastasis. Then, the prostate biopsy showed poorly differentiated small round cell malignant tumor and considered prostatic sarcoma. Immunohistochemistry showed MSI-H and dMMR prostatic sarcoma. Durvalumab alone was applied at a cycle of every 21 days (500 mg/day) for 18 months and achieved PR two months since the treatment. During the treatment, we didn't observe rash, immune-related pneumonia, hepatitis, and other adverse events. Also, no recurrence or metastasis was observed until now. Durvalumab is effective and safe in the treatment of advanced MSI-H or dMMR prostatic sarcoma in an elderly patient. It is promising to be an available choice for advanced prostate sarcoma, which is unsuitable for surgery, conventional chemotherapy, and radiotherapy.