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

Bibby BA, Reynolds JV, Maher SG - PLoS ONE (2015)

Bottom Line: MiRNAs have also been identified as modulators of key cellular pathways associated with resistance to CRT.In pre-treatment biopsies miR-330-5p was the most downregulated miRNA in patients who subsequently failed to respond to neo-CRT.However, miR-330-mediated alterations to the E2F1/p-AKT pathway were insufficient to significantly alter cellular sensitivity to chemotherapy (cisplatin and 5-flurouracil).

View Article: PubMed Central - PubMed

Affiliation: School of Biological, Biomedical and Environmental Sciences, University of Hull, Hull, United Kingdom.

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.

No MeSH data available.


Related in: MedlinePlus

miR-330-5p expression in pre-treatment diagnostic OAC tumour biopsies from responders vs. non-responders to neo-CRT.(A) MiR-330-5p expression is significantly lower in patients who do not respond to neo-CRT (TRG 4 and 5) when compared with responders (TRG 1 and 2). The two outlier values in the responder data set came from the two patients who were not clinical stage TNM T3. These two outlier values were biopsy specimens derived from tumours graded Tis and T2. Analysis was performed using the Mann Whitney U-test; **p<0.01. (B) MiR-330-5p expression is significantly lower in patients with TRG 4 (non-responders) compared to patients with TRG 1 and 2 (responders). Analysis was performed using the Mann Whitney U-test; *p < 0.05. Data are presented as the mean ± SEM.
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pone.0134180.g001: miR-330-5p expression in pre-treatment diagnostic OAC tumour biopsies from responders vs. non-responders to neo-CRT.(A) MiR-330-5p expression is significantly lower in patients who do not respond to neo-CRT (TRG 4 and 5) when compared with responders (TRG 1 and 2). The two outlier values in the responder data set came from the two patients who were not clinical stage TNM T3. These two outlier values were biopsy specimens derived from tumours graded Tis and T2. Analysis was performed using the Mann Whitney U-test; **p<0.01. (B) MiR-330-5p expression is significantly lower in patients with TRG 4 (non-responders) compared to patients with TRG 1 and 2 (responders). Analysis was performed using the Mann Whitney U-test; *p < 0.05. Data are presented as the mean ± SEM.

Mentions: In OAC patients, to identify miRNAs differentially expressed between responders and non-responders to neo-CRT, miRNA profiling arrays were used to analyse pre-treatment diagnostic biopsies. Of the 18 biopsy specimens analysed, 8 patients were responders and 10 patients were non-responders to neo-CRT. Following surgical resection the tissue removed was examined by a pathologist and assigned a TRG on a scale of 1–5. Patients categorised as TRG 1 (complete regression with no viable tumour cells evident) or TRG 2 (rare residual cancer cells) represented responders to CRT and TRG 4 (residual cancer outgrowing fibrosis) or TRG 5 (complete absence of regressive changes) represented non-responders. Patients categorised as TRG 3 were excluded for the purpose of this study. The patient cohort characteristics are outlined in Table 1. Of the 742 miRNA analysed in the array, 67 miRNAs were differentially expressed between the biopsy specimens of responders and non-responders. MiR-330-5p was the most differentially expressed miRNA between responders and non-responders, being significantly downregulated in the tumours of non-responders (Fig 1A). The expression of miR-330-5p was further assessed across the TRG groups; there was a significant downregulation in miR-330-5p expression in the TRG 4 group compared to TRG 2 group (Fig 1B). The downregulated expression of miR-330-5p in pre-treatment biopsies from non-responders, indicates a potential role in modulating targets and pathway associated with tumour response and sensitivity to the cytotoxic effects of CRT.


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

Bibby BA, Reynolds JV, Maher SG - PLoS ONE (2015)

miR-330-5p expression in pre-treatment diagnostic OAC tumour biopsies from responders vs. non-responders to neo-CRT.(A) MiR-330-5p expression is significantly lower in patients who do not respond to neo-CRT (TRG 4 and 5) when compared with responders (TRG 1 and 2). The two outlier values in the responder data set came from the two patients who were not clinical stage TNM T3. These two outlier values were biopsy specimens derived from tumours graded Tis and T2. Analysis was performed using the Mann Whitney U-test; **p<0.01. (B) MiR-330-5p expression is significantly lower in patients with TRG 4 (non-responders) compared to patients with TRG 1 and 2 (responders). Analysis was performed using the Mann Whitney U-test; *p < 0.05. Data are presented as the mean ± SEM.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4519309&req=5

pone.0134180.g001: miR-330-5p expression in pre-treatment diagnostic OAC tumour biopsies from responders vs. non-responders to neo-CRT.(A) MiR-330-5p expression is significantly lower in patients who do not respond to neo-CRT (TRG 4 and 5) when compared with responders (TRG 1 and 2). The two outlier values in the responder data set came from the two patients who were not clinical stage TNM T3. These two outlier values were biopsy specimens derived from tumours graded Tis and T2. Analysis was performed using the Mann Whitney U-test; **p<0.01. (B) MiR-330-5p expression is significantly lower in patients with TRG 4 (non-responders) compared to patients with TRG 1 and 2 (responders). Analysis was performed using the Mann Whitney U-test; *p < 0.05. Data are presented as the mean ± SEM.
Mentions: In OAC patients, to identify miRNAs differentially expressed between responders and non-responders to neo-CRT, miRNA profiling arrays were used to analyse pre-treatment diagnostic biopsies. Of the 18 biopsy specimens analysed, 8 patients were responders and 10 patients were non-responders to neo-CRT. Following surgical resection the tissue removed was examined by a pathologist and assigned a TRG on a scale of 1–5. Patients categorised as TRG 1 (complete regression with no viable tumour cells evident) or TRG 2 (rare residual cancer cells) represented responders to CRT and TRG 4 (residual cancer outgrowing fibrosis) or TRG 5 (complete absence of regressive changes) represented non-responders. Patients categorised as TRG 3 were excluded for the purpose of this study. The patient cohort characteristics are outlined in Table 1. Of the 742 miRNA analysed in the array, 67 miRNAs were differentially expressed between the biopsy specimens of responders and non-responders. MiR-330-5p was the most differentially expressed miRNA between responders and non-responders, being significantly downregulated in the tumours of non-responders (Fig 1A). The expression of miR-330-5p was further assessed across the TRG groups; there was a significant downregulation in miR-330-5p expression in the TRG 4 group compared to TRG 2 group (Fig 1B). The downregulated expression of miR-330-5p in pre-treatment biopsies from non-responders, indicates a potential role in modulating targets and pathway associated with tumour response and sensitivity to the cytotoxic effects of CRT.

Bottom Line: MiRNAs have also been identified as modulators of key cellular pathways associated with resistance to CRT.In pre-treatment biopsies miR-330-5p was the most downregulated miRNA in patients who subsequently failed to respond to neo-CRT.However, miR-330-mediated alterations to the E2F1/p-AKT pathway were insufficient to significantly alter cellular sensitivity to chemotherapy (cisplatin and 5-flurouracil).

View Article: PubMed Central - PubMed

Affiliation: School of Biological, Biomedical and Environmental Sciences, University of Hull, Hull, United Kingdom.

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.

No MeSH data available.


Related in: MedlinePlus