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MicroRNA profiling in oesophageal adenocarcinoma cell lines and patient serum samples reveals a role for miR-451a in radiation resistance [patients with Oesophageal Adenocarcinoma]

ABSTRACT: Many patients with Oesophageal Adenocarcinoma (OAC) that undergo chemoradiotherapy do not benefit from treatment due to therapy resistance. We therefore investigated the association of microRNAs, which regulate gene expression, with the response to individual treatments, focusing on radiation, to both better understand the mechanisms involved in resistance and to find potential biomarkers. Intrinsic radiation resistance and chemotherapy drug resistance were assessed in 8 OAC cell lines, and miRNA expression profiling was performed via high throughput qPCR. miRNAs were discovered that were either uniquely associated with resistance to radiation, cisplatin, or 5-FU, or were common to 2 or all 3 of the treatments. Target mRNA pathway analyses indicated several potential mechanisms of treatment resistance. miRNAs associated with the in-vitro treatment responses were then investigated for association with pathologic response to neoadjuvant chemoradiotherapy (nCRT) in pre-treatment serums of 39 patients with OAC. Hsa-miR-451a was associated uniquely with resistance to radiation treatment in the cell lines, and with the response to nCRT in patient serums. Inhibition of hsa-miR-451a in the radiation resistant OAC cell line OE19 increased radiosensitivity (Survival Fraction 73% vs. 87%, p=0.0003), and altered RNA expression. Pathway analysis of effected small non-coding RNAs and corresponding mRNA targets suggest potential mechanisms of radiation resistance in OAC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE160614 | GEO | 2020/12/15

REPOSITORIES: GEO

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Project description:Background: Neoadjuvant chemoradiotherapy (NCRT) is the treatment of choice in advanced rectal cancer, even though there are many patients who will not benefit from it. There are still no effective methods for predicting which patients will respond or not. The present study aimed to define the genomic profile of rectal tumors and to identify alterations that are predictive of response in order to optimize therapeutic strategies. Methods: Forty-eight candidates for NCRT were recruited and their pretherapy biopsies analyzed by array Comparative Genomic Hybridization (aCGH). Pathologic response was evaluated by tumor regression grade (TRG).Results: Both Smoothing and Hidden Markov Model (HMM) approaches identified similar alterations, with a prevalence of DNA gains. Non responsive patients had a different alteration profile from responsive ones, with a higher number of genome changes mainly located on 2q21, 7q21, 7q36, 13q12, 13q32-34, 16p13, 17p12 chromosomal regions. Conclusion: This exploratory study suggests that an in depth characterization of chromosomal alterations by aCGH would provide useful predictive information about response to NCRT and help to optimize therapy in rectal cancer patients. 48 samples included in the study were analyzed on whole genome BAC arrays with the aim to characterize genomic alterations and correlate them with the tumor response to therapy. The case series was composed by 15%,81% and 4% of uT2, uT3 and uT4 tumors, respectively. At the diagnosis 56% of patients had uN0 tumors and 44% uN+. 30%,13%, 23% and 34% of patients reached/mantained respectively ypT0, ypT1, ypT2 and ypT3. With regard to response to NCRT, according to TRG criteria proposed by Dworak, two group were defined: non responders (TRG0-2= 56%) and responders (TRG3-4=44%). Clinical and pathological parameters: uT: pre-therapy stage determined by ultrasounds techniques uN: pre-therapy lymph node status determined by ultrasounds techniques ypT: pathologic stage after a neoadjuvant treatment ypN: pathologic lymph node status after a neoadjuvant treatment

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MicroRNA profiling in oesophageal adenocarcinoma cell lines and patient serum samples reveals a role for miR-451a in radiation resistance [patients with Oesophageal Adenocarcinoma]

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