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Novel MicroRNAs regulating proliferation and apoptosis in uterine papillary serous carcinomas.

ABSTRACT: MicroRNAs (miRNAs) are endogenous, non-coding RNA transcripts that regulate gene expression. Here, we report 175 putative novel miRNAs identified in uterine cancers profiled by Next Generation Sequencing. Our data indicate that one of these putative miRNAs (BCM-173) is conserved across multiple species and is expressed at levels similar to known human miRNAs. Functionally, this miRNA promotes the growth and migration of uterine cancer cell lines by targeting vinculin and altering the distribution of focal adhesions. These results expand our insight into the repertoire of human miRNAs and identify novel pathways by which dysregulated miRNA expression promotes uterine cancer growth.

SUBMITTER: Mach CM

PROVIDER: S-EPMC3669647 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Novel MicroRNAs regulating proliferation and apoptosis in uterine papillary serous carcinomas.

Mach Claire M CM Kim Jong J Soibam Benjamin B Creighton Chad J CJ Hawkins Shannon M SM Zighelboim Israel I Goodfellow Paul P Gunaratne Preethi H PH Odunsi Kunle K Salem Philip A PA Anderson Matthew L ML

Cancer letters 20130226 2

MicroRNAs (miRNAs) are endogenous, non-coding RNA transcripts that regulate gene expression. Here, we report 175 putative novel miRNAs identified in uterine cancers profiled by Next Generation Sequencing. Our data indicate that one of these putative miRNAs (BCM-173) is conserved across multiple species and is expressed at levels similar to known human miRNAs. Functionally, this miRNA promotes the growth and migration of uterine cancer cell lines by targeting vinculin and altering the distributio ...[more]

PMID: 23454583

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Project description:ObjectiveStage I-II uterine papillary serous carcinoma (UPSC) has aggressive biological behavior and leads to poor prognosis. However, clinicopathologic risk factors to predict cancer-specific survival of patients with stage I-II UPSC were still unclear. This study was undertaken to develop a prediction model of survival in patients with early-stage UPSC.MethodsUsing Surveillance, Epidemiology, and End Results (SEER) database, 964 patients were identified with International Federation of Gynecology and Obstetrics (FIGO) stage I-II UPSC who underwent at least hysterectomy between 2004 and 2015. By considering competing risk events for survival outcomes, we used proportional subdistribution hazards regression to compare cancer-specific death (CSD) for all patients. Based on the results of univariate and multivariate analysis, the variables were selected to construct a predictive model; and the prediction results of the model were visualized using a nomogram to predict the cancer-specific survival and the response to adjuvant chemotherapy and radiotherapy of stage I-II UPSC patients.ResultsThe median age of the cohort was 67 years. One hundred and sixty five patients (17.1%) died of UPSC (CSD), while 8.6% of the patients died from other causes (non-CSD). On multivariate analysis, age ≥ 67 (HR = 1.45, P = .021), tumor size ≥ 2 cm (HR = 1.81, P = .014) and >10 regional nodes removed (HR = 0.52, P = .002) were significantly associated with cumulative incidence of CSD. In the age ≥67 cohort, FIGO stage IB-II was a risk factor for CSD (HR = 1.83, P = .036), and >10 lymph nodes removed was a protective factor (HR = 0.50, P = .01). Both adjuvant chemotherapy combined with radiotherapy and adjuvant chemotherapy alone decreased CSD of patients with stage I-II UPSC older than 67 years (HR = 0.47, P = .022; HR = 0.52, P = .024, respectively). The prediction model had great risk stratification ability as the high-risk group had higher cumulative incidence of CSD than the low-risk group (P < .001). In the high-risk group, patients with post-operative adjuvant chemoradiotherapy had improved CSD compared with patients who did not receive radiotherapy nor chemotherapy (P = .037). However, there was no such benefit in the low-risk group.ConclusionOur prediction model of CSD based on proportional subdistribution hazards regression showed a good performance in predicting the cancer-specific survival of early-stage UPSC patients and contributed to guide clinical treatment decision, helping oncologists and patients with early-stage UPSC to decide whether to choose adjuvant therapy or not.

Project description:HER2 overexpression/amplification is identified in up to 40% of uterine serous carcinomas (USC) and 10% of ovarian serous carcinomas (OSC). However, clinical trials using various HER2-targeted agents failed to show significant responses. FDA-approved HER2 assays target only the protein's intracellular domain (ICD) and not the extracellular domain (ECD). Previous quantitative studies in breast cancer by our group have shown that ICD of HER2 is expressed in some cases that do not express the HER2 ECD. We measured HER2 ICD and ECD in USC and OSC samples, and determined their relationship with clinico-pathologic characteristics and survival.We measured HER2 ICD and ECD levels in 2 cohorts of USC and OSC comprising 102 and 175 patients, respectively. HER2 antibodies targeting ICD (CB11) and ECD (SP3) were validated and standardized using the AQUA® method of quantitative immunofluorescence (QIF) and a previously reported HER2 standardization tissue microarray (TMA). Objective, population-based cut-points were used to stratify patients according to HER2 ICD/ECD status.In USC, 8% of patients with high HER2 ICD had low ECD levels (6/75 patients). In OSC, 42% of patients with high HER2 ICD had low ECD levels (29/69 patients). HER2 ICD/ECD status in USC and OSC was not significantly associated with major clinico-pathological features or survival.Using objective, domain-specific HER2 measurement, 8% of USC and 42% of OSC patients with high HER2 ICD levels do not show uniform overexpression of the ECD. This may be related to the presence of p95 HER2, an oncogenic fragment generated by full protein cleavage or alternative initiation of translation. These observations raise the possibility that USC/OSCs expressing low ECD despite being HER2-positive by ICD measurement, may benefit from therapies directed against the intracellular domain (e.g. lapatinib or afatinib) alone or in combination with extracellular domain-directed drugs (e.g. trastuzumab, pertuzumab, T-DM1).

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Novel MicroRNAs regulating proliferation and apoptosis in uterine papillary serous carcinomas.

Publications

Novel MicroRNAs regulating proliferation and apoptosis in uterine papillary serous carcinomas.

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