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    MicroRNA-330-5p as a Putative Modulator of Neoadjuvant Chemoradiotherapy Sensitivity in Oesophageal Adenocarcinoma.

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    Authors
    Bibby, Becky A S
    Reynolds, John V
    Maher, Stephen G
    Issue Date
    2015
    Keywords
    CANCER, OESOPAHGEAL
    MeSH
    Adenocarcinoma
    Adult
    Aged
    Biomarkers, Tumor
    Cell Line, Tumor
    Chemoradiotherapy, Adjuvant
    Down-Regulation
    Drug Resistance, Neoplasm
    E2F1 Transcription Factor
    Esophageal Neoplasms
    Female
    Humans
    Male
    MicroRNAs
    Middle Aged
    Proto-Oncogene Proteins c-akt
    RNA Interference
    Radiation Tolerance
    Treatment Failure
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    Citation
    MicroRNA-330-5p as a Putative Modulator of Neoadjuvant Chemoradiotherapy Sensitivity in Oesophageal Adenocarcinoma. 2015, 10 (7):e0134180 PLoS ONE
    Publisher
    PLoS ONE
    Journal
    PloS one
    URI
    http://hdl.handle.net/10147/621137
    DOI
    10.1371/journal.pone.0134180
    PubMed ID
    26221725
    Abstract
    Oesophageal adenocarcinoma (OAC) is the sixth most common cause of cancer deaths worldwide, and the 5-year survival rate for patients diagnosed with the disease is approximately 17%. The standard of care for locally advanced disease is neoadjuvant chemotherapy or, more commonly, combined neoadjuvant chemoradiation therapy (neo-CRT) prior to surgery. Unfortunately, ~60-70% of patients will fail to respond to neo-CRT. Therefore, the identification of biomarkers indicative of patient response to treatment has significant clinical implications in the stratification of patient treatment. Furthermore, understanding the molecular mechanisms underpinning tumour response and resistance to neo-CRT will contribute towards the identification of novel therapeutic targets for enhancing OAC sensitivity to CRT. MicroRNAs (miRNA/miR) function to regulate gene and protein expression and play a causal role in cancer development and progression. MiRNAs have also been identified as modulators of key cellular pathways associated with resistance to CRT. Here, to identify miRNAs associated with resistance to CRT, pre-treatment diagnostic biopsy specimens from patients with OAC were analysed using miRNA-profiling arrays. In pre-treatment biopsies miR-330-5p was the most downregulated miRNA in patients who subsequently failed to respond to neo-CRT. The role of miR-330 as a potential modulator of tumour response and sensitivity to CRT in OAC was further investigated in vitro. Through vector-based overexpression the E2F1/p-AKT survival pathway, as previously described, was confirmed as a target of miR-330 regulation. However, miR-330-mediated alterations to the E2F1/p-AKT pathway were insufficient to significantly alter cellular sensitivity to chemotherapy (cisplatin and 5-flurouracil). In contrast, silencing of miR-330-5p enhanced, albeit subtly, cellular resistance to clinically relevant doses of radiation. This study highlights the need for further investigation into the potential of miR-330-5p as a predictive biomarker of patient sensitivity to neo-CRT and as a novel therapeutic target for manipulating cellular sensitivity to neo-CRT in patients with OAC.
    Item Type
    Article
    Language
    en
    ISSN
    1932-6203
    ae974a485f413a2113503eed53cd6c53
    10.1371/journal.pone.0134180
    Scopus Count
    Collections
    St. James's Hospital

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