Project description:The tumor-initiating cell (TIC) model accounts for the phenotypic and functional heterogeneity among cancer cells found within human cancers. MicroRNAs (miRNAs) are key regulatory molecules frequently aberrantly expressed in tumors, and may play important roles in contributing towards tumor heterogeneity and TIC behavior. More recent efforts have focused on miRNAs for diagnosis and as targets for novel therapies. In this study, we identified the miRNAs, miR-1246 and miR-1290, which are crucial for the function of TICs, thereby driving cancer progression in human non-small cell lung cancer (NSCLC). These miRNAs are restricted to patient-derived tumorspheres and CD166+ primary tumor cells, both enriched for TICs. Loss of either miRNA impacted the tumorigenic potential of TICs and their ability to metastasize. Interestingly, longitudinal analyses of serum miR-1246 and miR-1290 levels correlated circulating levels of either miRNA to the clinical response seen in lung cancer patients to epidermal growth factor receptor (EGFR) tyrosine kinase inhibition, chemotherapy and radiotherapy. Functionally, direct inhibition of miR-1246 or miR-1290 with locked nucleic acid (LNA) administered systemically, could arrest the growth of established patient-derived tumors xenografted in immunocompromised mice, thus indicating these miRNAs are clinically useful as biomarkers for tracking disease progression and as therapeutic targets.
Project description:The tumor-initiating cell (TIC) model accounts for the phenotypic and functional heterogeneity among cancer cells found within human cancers. MicroRNAs (miRNAs) are key regulatory molecules frequently aberrantly expressed in tumors, and may play important roles in contributing towards tumor heterogeneity and TIC behavior. More recent efforts have focused on miRNAs for diagnosis and as targets for novel therapies. In this study, we identified the miRNAs, miR-1246 and miR-1290, which are crucial for the function of TICs, thereby driving cancer progression in human non-small cell lung cancer (NSCLC). These miRNAs are restricted to patient-derived tumorspheres and CD166+ primary tumor cells, both enriched for TICs. Loss of either miRNA impacted the tumorigenic potential of TICs and their ability to metastasize. Interestingly, longitudinal analyses of serum miR-1246 and miR-1290 levels correlated circulating levels of either miRNA to the clinical response seen in lung cancer patients to epidermal growth factor receptor (EGFR) tyrosine kinase inhibition, chemotherapy and radiotherapy. Functionally, direct inhibition of miR-1246 or miR-1290 with locked nucleic acid (LNA) administered systemically, could arrest the growth of established patient-derived tumors xenografted in immunocompromised mice, thus indicating these miRNAs are clinically useful as biomarkers for tracking disease progression and as therapeutic targets.
Project description:Colorectal cancer (CRC) ranks third in incidence and second in mortality among cancers worldwide. Emerging researches showed that microRNAs (miRNAs) play an important role in CRC progression. Here, we aimed to investigate the expression and regulatory mechanism of miR-1290 in CRC. miR-1290 is significantly overexpressed in CRC primary tissues and metastatic tissues compared to that in normal tissues, and up-regulated miR-1290 is correlated with poor overall survival (OS) of CRC patients. Functional experiments showed that miR-1290 can promote the proliferation, migration, invasion and inhibit apoptosis of CRC cells. Mechanistically, miR-1290 directly targets KLF9 and promotes the malignancy progression of CRC cells through regulating MMP9 and p53 expression, subsequently. In addition, high H3K4me3 levels in miR-1290 promoter region activate its transcription in CRC. In summary, our study demonstrated the expression and regulatory mechanism of miR-1290 in CRC which supports the notion that therapeutic targeting of miR-1290 may be a promising treatment approach for CRC patients.
Project description:Extracellular microRNAs (miRNAs) embedded in circulating exosomes may serves as prognostic biomarkers in cancer. This study was performed to identify and evaluate plasma exosomal miRNAs for prognostication in castration resistant prostate cancer (CRPC). RNA sequencing was performed to identify candidate exosomal miRNAs associated with overall survival in a screening cohort of 23 CRPC patients. Candidate miRNAs were further evaluated for prognosis using qRT-PCR in a follow-up cohort of 100 patients. Cox regression and Kaplan–Meier survival curve analysis were used to evaluate prognostic value of miRNA candidates with and without incorporation of clinical prognostic factors (age, Gleason score and time from androgen deprivation therapy to clinical progression). In the screening cohort, we obtained ~6.80 million mappable RNA reads per patient. Of those with normalized read counts ? 5, 43% were mapped to miRNAs for a total of 375 known and 57 novel miRNAs. Cox regression analysis identified an association of miR-1290, -1246, and -375 with overall survival (FDR<0.1). Of those, higher levels of miR-1290 and -375 were verified to be significantly associated with poor overall survival (p<0.004) in the follow-up cohort. The miR-1290/-375-based prediction model showed better performance with time-dependent area under the curve (AUC) =72% compared to clinical variable-based model with AUC=65%. Plasma exosomal miR-1290 and miR-375 are promising prognostic biomarkers for CRPC patients. Prospective validation is needed for further development of these candidate miRNAs.
Project description:MiR-1246 was found to promote tumorigenesis and metastasis in sevearl cancer types. In the context of tumor microenvironment, tumor-associated macrophages are a central part typically correlated with poor prognosis. We used microarray data to determine the gene expression profile in M2-like macrophages when treated with an overexpression of miR-1246 (conducted by miR-1246 mimic). As controls, we used either scambaled mimic control sequence, or a miR-1246 inhibitor.
Project description:Lung cancer is the leading cause of cancer death worldwide. The lack of specific and sensitive methods for early diagnosis as well as inadequate targeted therapies contribute to poor outcomes. A growing body of evidences suggests different roles of microRNAs including development and progression of lung cancer. The overexpression of the DNA repair protein apurinic/apyrimidinic endonuclease 1 (APE1) is an important cause of poor chemotherapeutic and its expression is able to predict the progression-free and overall survival in patients receiving platinum-containing chemotherapy. Recently, we have demonstrated APE1 involvement in miRNA biogenesis related to cancer progression. In this article, we report the identification of miRNAs that are modulated in lung cancer cells upon APE1 silencing. We defined a miRNA signature consisting of the 13 miRNAs, which strongly correlates with APE1 expression in lung cancer: miR-1246, miR-4488, miR-24, miR-183, miR-660, miR-130b, miR-543, miR-200c, miR-376c, miR-218, miR-146a, miR-92b and miR-33a. Gene ontology annotation and pathway analysis of the miRNA signature revealed its biological significance in cancer proliferation and survival. Among the miRNAs downregulated by APE1 is miRNA-33a-5p which targets Dicer, a major miRNA biogenesis gene whose expression is found to be downregulated in several tumours. We here validated Dicer as a direct functional target of miR-33a and profiled miR-33a, DICER and APE1 expression in clinical samples. Our findings suggest that APE1 may promote lung cancer progression through modulation of Dicer expression via miR-33a regulation. Our findings reveal new mechanistic insight into how APE1 functions in tumor biology.
Project description:We found that AGO2 suspends the formation of miRNA-single stranded (ss) DNA hybrid due to the high affinity interaction of AGO2-miRNA, being different from canonical miRNA guidance of AGO2 loading for mRNA. By this mechanism, we demonstrated that NamiRNA miR-1246 could promote MMP1 gene transcription to induce osteosarcoma cell metastasis. The observed metastasis features can be also extended to the transmission of miR-1246 enriched and carried by extracellular vesicles (EVs) to induce metastasis phenotypes of benign osteosarcoma cells. Collectively, we reveal that AGO2 senses and stabilizes miRNA-enhancer hybrids/loops to activate global gene expression and elucidate EV-carried miR-1246 plays important biological function to facilitate tumor metastasis.
Project description:To Identify of metastasis-related genes and metastasis-related miRNA in oral squamous cell carcinoma by miRNA profiling of HOC313-Parent, HOC313-LM and their respective exosomes carried out. As a result, miR-342-3p and -1246 were found candidate oncogenic miRNAs. To further identify the target genes of miR-1246 and miR-342-3p, we performed gene expression array analysis with HOC313-LM and HOC313-Parent (HOC313-P) transfected NT, miR-342-3p and miR-1246. Moreover, to identify tumor suppressor genes, gene expression profiles of each of transfected cells and HOC313-LM cells were analyzed by in silico analyses. As a result, DENND2D emerged as the possible target of miRN-1246. Extraction of difference of miRNA expression level between whole cell and exosomes of HOC313-Parent and HOC313-LM. Also, extraction of difference of gene expression level between high-metastatic subline (HOC313-LM) and low-metastatic subline (HOC313-P). Moreover the miRNA expression profiles and gene expression profiles were analyzed by in silico analyses.