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LncRNA-42060 Regulates Tamoxifen Sensitivity and Tumor Development via Regulating the miR-204-5p/SOX4 Axis in Canine Mammary Gland Tumor Cells.

ABSTRACT: Tamoxifen is the drug of choice for endocrine therapy of breast cancer. Its clinical use is limited by the development of drug resistance. There is increasing evidence that long non-coding RNAs (lncRNAs) are associated with tumor drug resistance. Therefore, we established two TAM-resistant cell lines, CHMp^TAM and CHMm^TAM. The different expression levels of lncRNA and miRNA in CHMm^TAM and CHMm were screened by RNA sequencing, and the lncRNA-miRNA interactions were analyzed. LncRNA ENSCAFG42060 (lnc-42060) was found to be significantly upregulated in drug-resistant cells and tumor tissues. Further functional validation revealed that the knockdown of lnc-42060 inhibited proliferation, migration, clone formation, restoration of TAM sensitivity, and reduction of stem cell formation in drug-resistant cells, whereas overexpression of lnc-4206 showed opposite results. Bioinformatics and dual-luciferase reporter gene assays confirmed that lnc-42060 could act as a sponge for miR-204-5p, further regulating SOX4 expression activity and thus influencing tumor cell progression. In conclusion, we screened lncRNAs and miRNAs associated with TAM resistance in canine mammary gland tumor cells for the first time. lnc-42060 served as a novel marker that may be used as an important biomarker for future diagnosis and treatment.

SUBMITTER: Xu E

PROVIDER: S-EPMC8255626 | biostudies-literature |

REPOSITORIES: biostudies-literature

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LncRNA-42060 Regulates Tamoxifen Sensitivity and Tumor Development via Regulating the miR-204-5p/SOX4 Axis in Canine Mammary Gland Tumor Cells

Project description:Tamoxifen is the drug of choice for endocrine therapy of breast cancer. Its clinical use is limited by the development of drug resistance. There is increasing evidence that long non-coding RNAs (lncRNAs) are associated with tumor drug resistance. Therefore, we established two TAM-resistant cell lines, CHMpTAM and CHMmTAM. The different expression levels of lncRNA and miRNA in CHMmTAM and CHMm were screened by RNA sequencing, and the lncRNA-miRNA interactions were analyzed. LncRNA ENSCAFG42060 (lnc-42060) was found to be significantly upregulated in drug-resistant cells and tumor tissues. Further functional validation revealed that the knockdown of lnc-42060 inhibited proliferation, migration, clone formation, restoration of TAM sensitivity, and reduction of stem cell formation in drug-resistant cells, whereas overexpression of lnc-4206 showed opposite results. Bioinformatics and dual-luciferase reporter gene assays confirmed that lnc-42060 could act as a sponge for miR-204-5p, further regulating SOX4 expression activity and thus influencing tumor cell progression. In conclusion, we screened lncRNAs and miRNAs associated with TAM resistance in canine mammary gland tumor cells for the first time. lnc-42060 served as a novel marker that may be used as an important biomarker for future diagnosis and treatment.

2021-07-14 | GSE164721 | GEO

LncRNA-42060 Regulates Tamoxifen Sensitivity and Tumor Development via Regulating the miR-204-5p/SOX4 Axis in Canine Mammary Gland Tumor Cells

Project description:LncRNA-42060 Regulates Tamoxifen Sensitivity and Tumor Development via Regulating the miR-204-5p/SOX4 Axis in Canine Mammary Gland Tumor Cells

| PRJNA691669 | ENA

<i>LncRNA NEAT1</i> regulated diabetic retinal epithelial-mesenchymal transition through regulating miR-204/SOX4 axis.

Project description:AimEpithelial-mesenchymal transition (EMT) of retinal pigment epithelium (RPE) cells is the key of the development of diabetic retinopathy (DR), and lncRNA NEAT1 could accelerate EMT in diabetic nephropathy. Meanwhile, as a diabetes susceptibility gene, whether sex-determining region Y-related (SRY) high-mobility group box 4 (SOX4) has relationship with lncRNA NEAT1 in DR remains unclear.MethodsFirstly, NEAT1, SOX4 and miR-204 were evaluated by qRT-PCR (quantitative reverse-transcriptase PCR) under high glucose condition. Then, cell viability, proliferation, migration and invasion were respectively detected by MTT, BrdU staining, wound healing and transwell assay after NEAT1 knockdown or miR-204 overexpression. Also, the EMT-related proteins were examined by western blot and cell immunofluorescence assay. In order to confirm the relationship between miR-204 and NEAT1 or SOX4, dual luciferase reporter gene assay was conducted. At the same time, the protein levels of SOX4 and EMT-related proteins were investigated by immunohistochemistry in vivo.ResultsHigh glucose upregulated NEAT1 and SOX4 and downregulated miR-204 in ARPE19 cells. NEAT1 knockdown or miR-204 overexpression inhibited the proliferation and EMT progression of ARPE19 cells induced by high glucose. NEAT1 was identified as a molecular sponge of miR-204 to increase the level of SOX4. The effect of NEAT1 knockdown on the progression of EMT under high glucose condition in ARPE19 cells could be reversed by miR-204 inhibitor. Also, NEAT1 knockdown inhibited retinal EMT in diabetic mice.ConclusionNEAT1 regulated the development of EMT in DR through miR-204/SOX4 pathway, which could provide reference for clinical prevention and treatment.

| S-EPMC8312494 | biostudies-literature

LncRNA DSCAM-AS1 Promotes Colon Cancer Cells Proliferation and Migration via Regulating the miR-204/SOX4 Axis.

Project description:Introduction:Long non-coding RNA (lncRNA) DSCAM-AS1 was reported to be aberrantly expressed and play pivotal roles in various human cancers. The aim of the present study was to investigate the expression and roles of DSCAM-AS1 in colon cancer (CC). Methods:Quantitative real-time PCR (qRT-PCR) was used to detect the expression of DSCAM-AS1, miR-204 and the mRNA level of SOX4. Cell proliferation and cell cycle were analyzed by MTT assay and flow cytometry, respectively. Transwell assay was used for migration capacity detection. Luciferase activity assay was conducted to verify the direct binding of DSCAM-AS1 and miR-204 or miR-204 and SOX4. The protein expression of SOX4 was determined by Western blot. Kaplan-Meier curves were calculated and the Log rank test was performed for the survival data analysis. Results:DSCAM-AS1 was significantly upregulated in CC and high expression of DSCAM-AS1 was associated with poor prognosis in patients with colon cancer. Knockdown of DSCAM-AS1 significantly suppressed CC cells proliferation and migration. In addition, DSCAM-AS acted as a molecular sponge for miR-204 and SOX4 was identified as a direct target of miR-204 in CC. Moreover, the rescue assay revealed that miR-204 inhibition partly abolished the effects of DSCAM-AS1 knockdown on CC cells proliferation, migration and SOX4 expression. Discussion:The present study demonstrated that DSCAM-AS1 acted as an oncogenic lncRNA in CC progression by regulating miR-204/SOX4 axis and DSCAM-AS1 may serve as a novel therapeutic target in the treatment of colon cancer.

| S-EPMC7293419 | biostudies-literature

Alteration of somatostatin receptor 2 expression in canine mammary gland tumor.

Project description:Somatostatin receptor 2 (SSTR2) is a negative regulator of cell proliferation in human breast cancer. Since there is little information about SSTR2 in canine mammary gland tumor (MGT), we clarified its distribution and expression level in normal mammary gland, benign MGT and malignant MGT. SSTR2 expression determined by immunohistochemical staining was observed in the cytoplasm of luminal epithelial cells. The intensity was negatively correlated with malignancy: normal tissues and some of the benign tumors had the highest levels, while the malignant tumors had little or no SSTR2 expression. As for the Western blotting, SSTR2 protein level in benign tumors was significantly lower than the normal mammary gland. On the other hand, SSTR2 protein levels in two of three malignant tumors were higher than the other groups. These results suggest that SSTR2 expression alters according to the malignancy of canine MGT.

| S-EPMC4638304 | biostudies-literature

MicroRNA and Messenger RNA Expression Profiles in Canine Mammary Gland Tumor.

Project description:Canine mammary gland tumor (CMT) is the most frequently diagnosed neoplasm in intact female dogs. As prognosis depends on the malignancy of tumors and metastasis levels, early and accurate diagnosis are crucial for prolongation of life expectancy. The genetic similarity of dogs with humans in addition to environmental and physiological similarities make them ideal models for the study of cancer. In this study, we analyzed differentially expressed microRNAs followed by RNA-Seq to investigate the alterations in mRNA levels based on the malignancy (benign, malignant) and the biopsy locations (tumors, surrounding normal tissues). We identified multiple breast cancer-related genes regardless of malignancy. We found cfa-miR-503 to be the only miRNA that showed altered expression in response to malignancy in CMTs. Although further validation is needed, cfa-miR-503 could be used as a potential diagnostic biomarker as well as a potential RNA-based anti-tumor drug in malignant CMTs.

| S-EPMC9917093 | biostudies-literature

MYC-activated lncRNA HNF1A-AS1 overexpression facilitates glioma progression via cooperating with miR-32-5p/SOX4 axis.

Project description:Mounting literatures have revealed the crucial effects of long noncoding RNA (lncRNA) in various cancers, including glioma. HNF1A-AS1, a novel lncRNA, is reported to modulate tumorigenesis and development of multiple cancers. However, the tumorigenic function of lncRNA HNF1A-AS1 in glioma remains largely unknown. quantitative reverse transcription and polymerase chain reaction and western blot assays were applied to evaluate the expression of relevant mRNAs and proteins. 5-Ethynyl-2'- deoxyuridine, terminal deoxynucleotidyl transferase dUTP nick-end labeling, flow cytometry, and transwell assays were conducted for examining the influence of HNF1A-AS1 on glioma cell functions. The relationship among RNAs was investigated by mechanical experiments. The results demonstrated that HNF1A-AS1 was predominantly highly expressed in glioma cell lines compared with nontumor glial epithelial cell, which was associated with the stimulation of transcription factor myelocytomatosis oncogene. Knockdown of HNF1A-AS1 remarkably inhibited glioma cells proliferation, migration, and invasion, while accelerating cell apoptosis in vitro. Mechanically, HNF1A-AS1 served as a miR-32-5p sponge. Moreover, SOX4 was discovered as a target of miR-32-5p. Inhibited miR-32-5p or upregulated SOX4 could markedly counteract the inhibitory effects of silencing HNF1A-AS1 on glioma malignant biological behaviors. HNF1A-AS1 exerted oncogenic property in glioma progression via upregulating miR-32-5p-mediated SOX4 expression, suggesting potential novel therapeutic target for future glioma treatment.

| S-EPMC7476832 | biostudies-literature

LncRNA HIF1A-AS2 accelerates malignant phenotypes of renal carcinoma by modulating miR-30a-5p/SOX4 axis as a ceRNA.

Project description:Several reports have proposed that lncRNAs, as potential biomarkers, participate in the progression and growth of malignant tumors. HIF1A-AS2 is a novel lncRNA and potential biomarker, involved in the genesis and development of carcinomas. However, the molecular mechanism of HIF1A-AS2 in renal carcinoma is unclear. The relative expression levels of HIF1A-AS2 and miR-30a-5p were detected using RT-qPCR in renal carcinoma tissues and cell lines. Using loss-of-function and overexpression, the biological effects of HIF1A-AS2 and miR-30a-5p in kidney carcinoma progression were characterized. Dual luciferase reporter gene analysis and Western blot were used to detect the potential mechanism of HIF1A-AS2 in renal carcinomas. HIF1A-AS2 was upregulated in kidney carcinoma tissues when compared with para-carcinoma tissues (P < 0.05). In addition, tumor size, tumor node mestastasis stage and differentiation were identified as being closely associated with HIF1A-AS2 expression (P < 0.05). Knockdown or overexpression of HIF1A-AS2 either restrained or promoted the malignant phenotype and WNT/β-catenin signaling in renal carcinoma cells (P < 0.05). MiR-30a-5p was downregulated in renal cancers and partially reversed HIF1A-AS2 functions in malignant renal tumor cells. HIF1A-AS2 acted as a microRNA sponge that actively regulated the relative expression of SOX4 in sponging miR-30a-5p and subsequently increased the malignant phenotypes of renal carcinomas. HIF1A-AS2 showed a carcinogenic effect and miR-30a-5p acted as an antagonist of the anti-oncogene effects in the pathogenesis of renal carcinomas. The HIF1A-AS2-miR-30a-5p-SOX4 axis was associated with the malignant progression and development of renal carcinoma. The relative expression of HIF1A-AS2 was negatively correlated with the expression of miR-30a-5p, and was closely correlated with SOX4 mRNA levels in renal cancers.

| S-EPMC8185866 | biostudies-literature

The influence of tamoxifen on normal mouse mammary gland homeostasis.

Project description:IntroductionLineage tracing using inducible genetic labeling has emerged to be a powerful method for interrogating the developmental fate of cells in intact tissues. A common induction mechanism is the use of tamoxifen-dependent Cre recombinase (CreER and CreERT2), but the effects of tamoxifen at doses normally used in lineage-tracing studies on normal adult mammary gland homeostasis are not known.MethodsWe used flow cytometry and immunostaining of intact glands to determine whether varying doses of tamoxifen skew the distribution and the apoptosis and proliferation status of different types of mammary epithelial cells in vivo. We also examined how tamoxifen influences the number of progenitor and mammary repopulating units (MRUs).ResultsOur results indicate that ≥5 mg/25 g body weight of tamoxifen induces a transient increase in cell proliferation and in the number of basal cells in the adult mammary epithelium up to 7 days after tamoxifen administration. However, in the medium term (3 weeks), all doses of tamoxifen≥1 mg/25 g body weight result in a decrease in the number of basal and EpCAM+CD49b- luminal cells and a decrease in progenitor cell function. Tamoxifen at doses≥5 mg/25 g body weight induced a transient increase in caspase-3-mediated apoptotic cell death within the mammary epithelium. However, mammary epithelial cell numbers in all subpopulations were restored to their original levels by 8 weeks. No long-lasting effects of tamoxifen on MRU numbers or on pubertal ductal development were observed.ConclusionTamoxifen can skew the distribution of mammary cell types in a dose-dependent manner, and thus caution must be taken when interpreting lineage-tracing studies using high doses of tamoxifen, particularly when short-duration analyses of a quantitative nature are being performed.

| S-EPMC4303226 | biostudies-literature

Exosome proteomes reveal glycolysis-related enzyme enrichment in primary canine mammary gland tumor compared to metastases.

Project description:ObjectiveNumerous evidence has highlighted the differences between primary tumors and metastases. Nonetheless, the differences in exosomal proteins derived from primary tumor and metastases remain elusive. Here, we aimed to identify differentially expressed exosomal proteins from primary canine mammary gland tumor and metastases to understand how they shape their own tumor microenvironment.MethodsWe clearly distinguished primary canine mammary gland tumors (CHMp) from metastases (CHMm) and profiled the proteins within their secreted exosomes using LC-MS/MS. Moreover, the abundance of glycolysis enzymes (GPI, LDHA) in CHMp exosome was verified with Western blotting, To broaden the scope, we extended to human colorectal cancer-derived exosomes (SW480 vs. SW620) for comparison.ResultsWe identified significant differences in 87 and 65 proteins derived from CHMp and CHMm, respectively. Notably, glycolysis enzymes (GPI, LDHA, LDHB, TPI1, and ALDOA) showed specific enrichment in exosomes from the primary tumor.ConclusionWe observed significant differences in the cellular proteome between primary tumors and metastases, and intriguingly, we identified a parallel heterogeneity the protein composition of exosomes. Specifically, we reported that glycolysis enzymes were significantly enriched in CHMp exosomes compared to CHMm exosomes. We further demonstrated that this quantitative difference in glycolysis enzymes persisted across primary and metastases, extending to human colorectal cancer-derived exosomes (SW480 vs. SW620). Our findings of the specific enrichment of glycolysis enzymes in primary tumor-derived exosomes contribute to a better understanding of tumor microenvironment modulation and heterogeneity between primary tumors and metastases.

| S-EPMC10900604 | biostudies-literature

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