Cisplatin-based chemotherapy is commonly used for the clinical treatment of patients with non-small cell lung cancer (NSCLC). However, the anti-tumor efficacy of cisplatin is limited by poor clinical response and the development of chemoresistance. At present, the underlying mechanism for cisplatin resistance remains unclear. In the present study, it was identified that metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a long non-coding RNA that has been demonstrated to function as an oncogene, was increased in tumor tissues from patients with cisplatin-resistant NSCLC. In addition, the MALAT1 level was increased in A549rCDDP cells compared with the parental A549 cells. Silencing of MALAT1 sensitized A549rCDDP cells to cisplatin treatment, while overexpression of MALAT1 in A549 cells decreased their sensitivity towards cisplatin. Through analysis of the gene expression in patient samples, a decrease in miR-145 and an increase in Kruppel-like factor 4 (KLF4) in tumor tissues compared with adjacent normal tissues was observed. A negative association between MALAT1 and miR-145 was also identified in A549 cells and A549rCDDP cells. Furthermore, reverse transcription quantitative polymerase chain reaction and western blotting identified that KLF4 was positively and negatively regulated by MALAT1 and miR-145, respectively. The direct regulatory association between MALAT1 and miR-145 and the target gene KLF4 was additionally confirmed using a luciferase reporter assay. Knockdown of MALAT1 reversed cisplatin resistance in A549rCDDP cells. Taken together, these data indicated that MALAT1 decreased the sensitivity of NSCLC to cisplatin via the regulation of miR-145 and KLF4.
Transforming growth factor-β (TGF-β) is composed of three isoforms, TGF-β1, TGF-β2, and TGF-β3. TGF-β1 is a cytokine with multiple biological functions that has been studied extensively. It plays an important role in regulating the differentiation of immune cells and maintaining immune cell functions and immune homeostasis. Pregnancy is a carefully regulated process. Controlled invasion of trophoblasts, precise coordination of immune cells and cytokines, and crosstalk between trophoblasts and immune cells play vital roles in the establishment and maintenance of normal pregnancy. In this systematic review, we summarize the role of TGF-β1 in regulating fetal-maternal immune tolerance in healthy and pathological pregnancies. During healthy pregnancy, TGF-β1 induces the production of regulatory T cells (Tregs), maintains the immunosuppressive function of Tregs, mediates the balance of M1/M2 macrophages, and regulates the function of NK cells, thus participating in maintaining fetal-maternal immune tolerance. In addition, some studies have shown that TGF-β1 is dysregulated in patients with recurrent spontaneous abortion or preeclampsia. TGF-β1 may play a role in the occurrence and development of these diseases and may be a potential target for the treatment of these diseases.
Background Cytotoxic T-lymphocyte associated protein 4 (CTLA4) inhibitors have been shown to significantly prolong the overall survival (OS) in a wide range of cancers. However, its application in clear cell renal cell carcinoma (ccRCC) is limited due to the therapy response, and the prognostic value of CTLA4 in ccRCC has not been investigated in detail. Methods By using immunohistochemistry, Kaplan–Meier (K–M) analysis, uni- and multi-variate Cox analysis, we comprehensively and systematically studied the prognostic value of CTLA4 in ccRCC. Then, we applied Gene Ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG) and CIBERSORT, ESTIMATE algorithm, ssGSEA and somatic mutation analyses to reveal the impact of CTLA4 on the landscape of tumor-infiltrating lymphocytes (TILs) infiltration and genetic mutation. Besides, given current concerns caused by combined immunotherapy, we also investigated the relationship between CTLA4 and other immune checkpoints. Results In vitro experiment and data mining showed that, CTLA4 was up-regulated in ccRCC tissues and closely related to the disease progression as well as a poor prognosis. Deeper researches demonstrated that CTLA4 regulates T cell activation and was significantly linked to TIL-abundant tumor microenvironment (TME), but was accompanied by an immunosuppressed phenotype. Mutation analysis showed that CTLA4 was associated with more frequent BRCA-associated protein 1 (BAP1) mutation. Moreover, we found that CTLA4 was markedly correlated with multiple immune checkpoints, which suggested that ccRCC patients with high expressed CTLA4 may benefit more from immune checkpoint blockades (ICBs) combined therapy. Conclusion CTLA4 has a profound impact on the landscape of TILs and genetic mutation, and can be used as the biomarker with high prognosis value in ccRCC.
Background: Cervical carcinoma is one of the most common malignant gynecological tumors and is associated with high rates of morbidity and mortality. Early diagnosis and early treatment can reduce the mortality rate of cervical cancer. However, there is still no specific biomarkers for the diagnosis and detection of cervical cancer prognosis. Therefore, it is greatly urgent in searching biomarkers correlated with the diagnosis and prognosis of cervical cancer. Results: The mRNA and microRNA expression profile datasets (GSE7803, GSE9750, GSE63514, and GSE30656) were downloaded from the Gene Expression Omnibus database (GEO). The three microarray datasets were integrated to one via integrated bioinformatics. Differentially expressed genes (DEGs) and microRNAs (DEMs) were obtained by R software. The protein–protein interaction (PPI) networks of the DEGs were performed from the STRING database and further visualized by Cytoscape software. A total of 83 DEGs and 14 DEMs were screened from the microarray expression profile datasets. The miRNAs validated to be associated with cervical cancer were obtained using HMDD online website and the target genes of DEMs were identified using the miRWalk2.0 online database. ESR1, PPP1R3C, NSG1 , and TMPRSS11D were the gene targets of hsa-miR-21; the targets of hsa-miR-16 were GYS2, ENDOU , and KLF4 . These targets were all downregulated in cervical cancer. Finally, we verified the expression of those targets in cervical tissues from TCGA and GTEx databases and analyzed their relationship with survival of cervical cancer patients. In the end, the expression of key genes in cervical cancer tissues was verified via experiment method, we found KLF4 and ESR1 were downregulated in tumor tissues. Conclusion: This study indicates that KLF4 and ESR1 are downregulated by the upregulated miR21 and miRNA16 in cervical cancer, respectively, using bioinformatics analysis, and the lower expression of KLF4 and ESR1 is closely related to the poor prognosis. They might be of clinical significance for the diagnosis and prognosis of cervical cancer, and provide effective targets for the treatment of cervical cancer.
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