SLC1A5 enhances malignant phenotypes through modulating ferroptosis status and immune microenvironment in glioma.

Glioma is the most common type of primary malignant tumor in the central nervous system with limited treatment satisfaction. Finding new therapeutic targets has remained a major challenge. Ferroptosis is a novel and distinct type of programmed cell death, playing a regulatory role in the progression of tumors. However, the role of ferroptosis or ferroptosis-related genes (FRGs) in glioma progression has not been extensively studied. In our study, a novel ferroptosis-related prognostic model, including 7 genes, was established, in which patients classified into the high-risk group had more immuno-suppressive status and worse prognosis. Among these 7 genes, we screened solute carrier family 1 member 5 (SLC1A5), an FRG, as a possible new target for glioma treatment. Our results showed that the expression of SLC1A5 was significantly upregulated in glioblastoma tissues compared with the low-grade gliomas. In addition, SLC1A5 knockdown could significantly inhibit glioma cell proliferation and invasion, and reduce the sensitivity of ferroptosis via the GPX4-dependent pathway. Furthermore, SLC1A5 was found to be related to immune response and SLC1A5 knockdown decreased the infiltration and M2 polarization of tumor-associated macrophages. Pharmacological inhibition of SLC1A5 by V9302 was confirmed to promote the efficacy of anti-PD-1 therapy. Overall, we developed a novel prognostic model for glioma based on the seven-FRGs signature, which could apply to glioma prognostic and immune status prediction. Besides, SLC1A5 in the model could regulate the proliferation, invasion, ferroptosis and immune state in glioma, and be applied as a prognostic biomarker and potential therapeutic target for glioma.

Immune Gene Signatures and Immunotypes in Immune Microenvironment Are Associated With Glioma Prognose.

Glioma is the most common primary malignant brain tumor in adults with very poor prognosis. The limited new therapeutic strategies for glioma patients can be partially attributed to the complex tumor microenvironment. However, knowledge about the glioma immune microenvironment and the associated regulatory mechanisms is still lacking. In this study, we found that, different immune subtypes have a significant impact on patient survival. Glioma patients with a high immune response subtype had a shorter survival compared with patients with a low immune response subtype. Moreover, the number of B cell, T cell, NK cell, and in particular, the macrophage in the immune microenvironment of patients with a high immune response subtype were significantly enhanced. In addition, 132 genes were found to be related to glioma immunity. The functional analysis and verification of seven core genes showed that their expression levels were significantly correlated with the prognosis of glioma patients, and the results were consistent at tissue levels. These findings indicated that the glioma immune microenvironment was significantly correlated with the prognosis of glioma patients and multiple genes were involved in regulating the progression of glioma. The identified genes could be used to stratify glioma patients based on immune subgroup analysis, which may guide their clinical treatment regimen.

Overexpression of TMEM47 Induces Tamoxifen Resistance in Human Breast Cancer Cells.

BACKGROUND: Tamoxifen (TAM) is the eminent first-line drug for endocrine therapy of hormone receptor positive premenopausal breast cancer and reduces the risk of recurrence by ∼50%. However, many patients developed TAM resistance and their diseases recurred. Our previous study on transcriptome profile of TAM resistant breast cancer cells revealed that the TMEM47 is one of the most significantly differentially expressed genes. The mechanism of how TMEM47 is involved in TAM resistance was not known. METHODS: We constructed a mammal breast cancer cell line, in which TMEM47 was stably overexpressed (TMEM47-OE/MCF-7), to further verify the role of TMEM47 in TAM resistance. siRNA targeting TMEM47 was transfected into TAMR / MCF-7 cells by Liposome. TMEM47 expression was validated on mRNA and protein level by qRT-PCR and western blotting. We tested the cytotoxicity of TAM in the cells. Apoptosis was detected by flow cytometry. RESULTS: Compared to the MCF7 cells, TMEM47 mRNA was significantly up regulated more than 6 folds in the TAMR/MCF7 cells and so its protein. TMEM47 expression level in TMEM47-OE/MCF-7 was similar as in the TAMR/MCF-7 cells. The 50% inhibitory concentration (IC50) value (mean ± SD) of TAM in MCF-7, TAMR/MCF-7 and TMEM47-OE/MCF-7 cells was 1.58 ± 0.19, 2.74 ± 0.24 and 3.12 ± 0.32 µÎ³/mL, respectively. The apoptosis rates of TAMR/MCF-7 and TMEM47-OE/MCF-7 cell lines were significantly lower than that of MCF-7 cells. After 24 and 48 hours TAM treatments, cell viability was significantly inhibitied in TMEM47 knockdown TAMR/MCF7 cells (P < 0.01). Consistant with the decreased cell viability, the apoptosis rate in TMEM47 knockdown TAMR/MCF-7 cells was significantly increased. CONCLUSIONS: Our results suggest that overexpression of TMEM47 in MCF-7 cells acquired TAM resistance to those cells, and knockdown of TMEM47 in TAMR/MCF-7 cells reversed their resistance to TAM. TMEM47 might confer TAM resistance on MCF-7 cells through the inhibition of apoptosis.

MiR-1254 and MEGF6 regulates oxaliplatin resistance in human colorectal cancer cells.

Colorectal cancer (CRC) remains one of the deadliest diseases in the whole world. Cancer recurrence and chemotherapeutic drug resistance limit the overall survival rate of patients with CRC. This study aimed to discover the latent miRNAs and genes associated with oxaliplatin resistance in CRC cells. The study found that miR-1254 is upregulated in oxaliplatin-resistant CRC cell line HCT116-R compared with its parental cell line HCT116 by transcriptome sequencing and small RNA sequencing. Meanwhile, MEGF6 (multiple EGF-like domains 6) was downregulated in HCT116-R cells. Transient transfection of miR-1254 mimics significantly reduced cell apoptosis, increased HCT116 tolerance to oxaliplatin, and enhanced MEGF6 expression. Furthermore, transfection of miR-1254 inhibitor increased apoptosis, decreased HCT116-R tolerance to oxaliplatin, and reduced MEGF6 expression. In addition, transient transfection of SiMEGF6 enhanced HCT116 cell resistance to oxaliplatin and reduced cell apoptosis. In summary, MEGF6 is a latent functional target of miR-1254 in regulating oxaliplatin resistance and apoptosis in human CRC cells, suggesting a potential therapeutic target for CRC.

MiR-483-3p regulates oxaliplatin resistance by targeting FAM171B in human colorectal cancer cells.

Oxaliplatin resistance limits the efficiency of treatment for colorectal cancer (CRC). Studies have shown that abnormal expression of microRNAs (miRNAs) were associated with tumorigenesis, cancer development and chemoresistance. The purpose of this study was to identify potential miRNAs related to oxaliplatin resistance in CRC cells. In this work, using small RNA sequencing (small RNA-Seq) and transcriptome sequencing (RNA-Seq), we found that down-regulated miR-483-3p was concurrent with up-regulated FAM171B in oxaliplatin-resistant colorectal cancer cell line HCT116/L as compared with its parental cell line HCT116. Transient transfection of miR-483-3p mimics markedly decreased the levels of FAM171B and restored oxaliplatin responsiveness of HCT116/L cells, and this alteration enhanced cell apoptosis and weakened cell migration. Whereas miR-483-3p inhibitor dramatically promoted the expression of FAM171B and enhanced oxaliplatin resistance of HCT116 cells by repressing cell apoptosis. Furthermore, knockdown of FAM171B in HCT116/L cells could also sensitize its reaction of the treatment with oxaliplatin, which was verified by the reduced cell migration. These findings demonstrate that FAM171B is a functional target of miR-483-3p in the regulation of oxaliplatin resistance in human CRC cells.