microRNA-451a regulates colorectal cancer proliferation in response to radiation

Rebecca Ruhl, Shushan Rana, Katherine Kelley, Cristina Espinosa-Diez, Clayton Hudson, Christian Lanciault, Charles Thomas, Vassiliki Tsikitis, Sudarshan Anand

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Background: Colorectal cancer (CRC) is a leading cause of cancer-related death. The biologic response of CRC to standard of care adjuvant therapies such as chemotherapy and radiation are poorly understood. MicroRNAs (miRs) have been shown to affect CRC progression and metastasis. Therefore, we hypothesized that specific miRs modulate CRC response to chemoradiation. Methods: In this study, we used miR expression profiling and discovered a set of microRNAs upregulated rapidly in response to either a single 2 Gy dose fraction or a 10 Gy dose of γ-radiation in mouse colorectal carcinoma models. We used gain and loss-of-function studies in 2D and 3Dcell proliferation assays and colony formation assays to understand the role of the top miR candidate from our profiling. We used Student's T-tests for simple comparisons and two-factor ANOVA for evaluating significance. Results: The most upregulated candidate at early time points in our signature, miR-451a inhibited tumor cell proliferation and attenuated surviving fraction in longer-term cultures. Conversely, inhibition of miR-451a increased proliferation, tumorsphere formation, and surviving fraction of tumor cells. Using a bioinformatics approach, we identified four genes, CAB39, EMSY, MEX3C, and EREG, as targets of miR-451a. Transfection of miR-451a decreased both mRNA and protein levels of these targets. Importantly, we found miR-451a expression was high and CAB39, EMSY levels were low in a small subset of rectal cancer patients who had a partial response to chemoradiation when compared to patients that had no response. Finally, analysis of a TCGA colorectal cancer dataset revealed that CAB39 and EMSY are upregulated at the protein level in a significant number of CRC patients. Higher levels of CAB39 and EMSY correlated with poorer overall survival. Conclusions: Taken together, our data indicates miR-451a is induced by radiation and may influence colorectal carcinoma proliferation via CAB39 and EMSY pathways.

Original languageEnglish (US)
Article number517
JournalBMC Cancer
Volume18
Issue number1
DOIs
StatePublished - May 3 2018

Fingerprint

MicroRNAs
Colorectal Neoplasms
Radiation
Radiation Dosage
Neoplasms
Standard of Care
Rectal Neoplasms
Computational Biology
Transfection
Analysis of Variance
Proteins
Cell Proliferation
Students
Neoplasm Metastasis
Drug Therapy
Messenger RNA
Survival
Genes

Keywords

  • CAB39
  • Colorectal cancer
  • EMSY
  • MicroRNAs
  • Radiation therapy

ASJC Scopus subject areas

  • Oncology
  • Genetics
  • Cancer Research

Cite this

microRNA-451a regulates colorectal cancer proliferation in response to radiation. / Ruhl, Rebecca; Rana, Shushan; Kelley, Katherine; Espinosa-Diez, Cristina; Hudson, Clayton; Lanciault, Christian; Thomas, Charles; Tsikitis, Vassiliki; Anand, Sudarshan.

In: BMC Cancer, Vol. 18, No. 1, 517, 03.05.2018.

Research output: Contribution to journalArticle

Ruhl, Rebecca ; Rana, Shushan ; Kelley, Katherine ; Espinosa-Diez, Cristina ; Hudson, Clayton ; Lanciault, Christian ; Thomas, Charles ; Tsikitis, Vassiliki ; Anand, Sudarshan. / microRNA-451a regulates colorectal cancer proliferation in response to radiation. In: BMC Cancer. 2018 ; Vol. 18, No. 1.
@article{2f18776bfc3c431a8417058dfc8a8620,
title = "microRNA-451a regulates colorectal cancer proliferation in response to radiation",
abstract = "Background: Colorectal cancer (CRC) is a leading cause of cancer-related death. The biologic response of CRC to standard of care adjuvant therapies such as chemotherapy and radiation are poorly understood. MicroRNAs (miRs) have been shown to affect CRC progression and metastasis. Therefore, we hypothesized that specific miRs modulate CRC response to chemoradiation. Methods: In this study, we used miR expression profiling and discovered a set of microRNAs upregulated rapidly in response to either a single 2 Gy dose fraction or a 10 Gy dose of γ-radiation in mouse colorectal carcinoma models. We used gain and loss-of-function studies in 2D and 3Dcell proliferation assays and colony formation assays to understand the role of the top miR candidate from our profiling. We used Student's T-tests for simple comparisons and two-factor ANOVA for evaluating significance. Results: The most upregulated candidate at early time points in our signature, miR-451a inhibited tumor cell proliferation and attenuated surviving fraction in longer-term cultures. Conversely, inhibition of miR-451a increased proliferation, tumorsphere formation, and surviving fraction of tumor cells. Using a bioinformatics approach, we identified four genes, CAB39, EMSY, MEX3C, and EREG, as targets of miR-451a. Transfection of miR-451a decreased both mRNA and protein levels of these targets. Importantly, we found miR-451a expression was high and CAB39, EMSY levels were low in a small subset of rectal cancer patients who had a partial response to chemoradiation when compared to patients that had no response. Finally, analysis of a TCGA colorectal cancer dataset revealed that CAB39 and EMSY are upregulated at the protein level in a significant number of CRC patients. Higher levels of CAB39 and EMSY correlated with poorer overall survival. Conclusions: Taken together, our data indicates miR-451a is induced by radiation and may influence colorectal carcinoma proliferation via CAB39 and EMSY pathways.",
keywords = "CAB39, Colorectal cancer, EMSY, MicroRNAs, Radiation therapy",
author = "Rebecca Ruhl and Shushan Rana and Katherine Kelley and Cristina Espinosa-Diez and Clayton Hudson and Christian Lanciault and Charles Thomas and Vassiliki Tsikitis and Sudarshan Anand",
year = "2018",
month = "5",
day = "3",
doi = "10.1186/s12885-018-4370-1",
language = "English (US)",
volume = "18",
journal = "BMC Cancer",
issn = "1471-2407",
publisher = "BioMed Central",
number = "1",

}

TY - JOUR

T1 - microRNA-451a regulates colorectal cancer proliferation in response to radiation

AU - Ruhl, Rebecca

AU - Rana, Shushan

AU - Kelley, Katherine

AU - Espinosa-Diez, Cristina

AU - Hudson, Clayton

AU - Lanciault, Christian

AU - Thomas, Charles

AU - Tsikitis, Vassiliki

AU - Anand, Sudarshan

PY - 2018/5/3

Y1 - 2018/5/3

N2 - Background: Colorectal cancer (CRC) is a leading cause of cancer-related death. The biologic response of CRC to standard of care adjuvant therapies such as chemotherapy and radiation are poorly understood. MicroRNAs (miRs) have been shown to affect CRC progression and metastasis. Therefore, we hypothesized that specific miRs modulate CRC response to chemoradiation. Methods: In this study, we used miR expression profiling and discovered a set of microRNAs upregulated rapidly in response to either a single 2 Gy dose fraction or a 10 Gy dose of γ-radiation in mouse colorectal carcinoma models. We used gain and loss-of-function studies in 2D and 3Dcell proliferation assays and colony formation assays to understand the role of the top miR candidate from our profiling. We used Student's T-tests for simple comparisons and two-factor ANOVA for evaluating significance. Results: The most upregulated candidate at early time points in our signature, miR-451a inhibited tumor cell proliferation and attenuated surviving fraction in longer-term cultures. Conversely, inhibition of miR-451a increased proliferation, tumorsphere formation, and surviving fraction of tumor cells. Using a bioinformatics approach, we identified four genes, CAB39, EMSY, MEX3C, and EREG, as targets of miR-451a. Transfection of miR-451a decreased both mRNA and protein levels of these targets. Importantly, we found miR-451a expression was high and CAB39, EMSY levels were low in a small subset of rectal cancer patients who had a partial response to chemoradiation when compared to patients that had no response. Finally, analysis of a TCGA colorectal cancer dataset revealed that CAB39 and EMSY are upregulated at the protein level in a significant number of CRC patients. Higher levels of CAB39 and EMSY correlated with poorer overall survival. Conclusions: Taken together, our data indicates miR-451a is induced by radiation and may influence colorectal carcinoma proliferation via CAB39 and EMSY pathways.

AB - Background: Colorectal cancer (CRC) is a leading cause of cancer-related death. The biologic response of CRC to standard of care adjuvant therapies such as chemotherapy and radiation are poorly understood. MicroRNAs (miRs) have been shown to affect CRC progression and metastasis. Therefore, we hypothesized that specific miRs modulate CRC response to chemoradiation. Methods: In this study, we used miR expression profiling and discovered a set of microRNAs upregulated rapidly in response to either a single 2 Gy dose fraction or a 10 Gy dose of γ-radiation in mouse colorectal carcinoma models. We used gain and loss-of-function studies in 2D and 3Dcell proliferation assays and colony formation assays to understand the role of the top miR candidate from our profiling. We used Student's T-tests for simple comparisons and two-factor ANOVA for evaluating significance. Results: The most upregulated candidate at early time points in our signature, miR-451a inhibited tumor cell proliferation and attenuated surviving fraction in longer-term cultures. Conversely, inhibition of miR-451a increased proliferation, tumorsphere formation, and surviving fraction of tumor cells. Using a bioinformatics approach, we identified four genes, CAB39, EMSY, MEX3C, and EREG, as targets of miR-451a. Transfection of miR-451a decreased both mRNA and protein levels of these targets. Importantly, we found miR-451a expression was high and CAB39, EMSY levels were low in a small subset of rectal cancer patients who had a partial response to chemoradiation when compared to patients that had no response. Finally, analysis of a TCGA colorectal cancer dataset revealed that CAB39 and EMSY are upregulated at the protein level in a significant number of CRC patients. Higher levels of CAB39 and EMSY correlated with poorer overall survival. Conclusions: Taken together, our data indicates miR-451a is induced by radiation and may influence colorectal carcinoma proliferation via CAB39 and EMSY pathways.

KW - CAB39

KW - Colorectal cancer

KW - EMSY

KW - MicroRNAs

KW - Radiation therapy

UR - http://www.scopus.com/inward/record.url?scp=85046274248&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85046274248&partnerID=8YFLogxK

U2 - 10.1186/s12885-018-4370-1

DO - 10.1186/s12885-018-4370-1

M3 - Article

C2 - 29720118

AN - SCOPUS:85046274248

VL - 18

JO - BMC Cancer

JF - BMC Cancer

SN - 1471-2407

IS - 1

M1 - 517

ER -