Human colon cancer profiles show differential microRNA expression depending on mismatch repair status and are characteristic of undifferentiated proliferative states

Aaron L. Sarver, Amy J. French, Pedro M. Borralho, Venugopal Thayanithy, Ann L Oberg, Kevin A T Silverstein, Bruce W. Morlan, Shaun M. Riska, Lisa Allyn Boardman, Julie M Cunningham, Subbaya Subramanian, Liang Wang, Thomas Christopher Smyrk, Cecilia M P Rodrigues, Stephen N Thibodeau, Clifford J. Steer

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Abstract

Background: Colon cancer arises from the accumulation of multiple genetic and epigenetic alterations to normal colonic tissue. microRNAs (miRNAs) are small, non-coding regulatory RNAs that post-transcriptionally regulate gene expression. Differential miRNA expression in cancer versus normal tissue is a common event and may be pivotal for tumor onset and progression. Methods: To identify miRNAs that are differentially expressed in tumors and tumor subtypes, we carried out highly sensitive expression profiling of 735 miRNAs on samples obtained from a statistically powerful set of tumors (n = 80) and normal colon tissue (n = 28) and validated a subset of this data by qRT-PCR. Results: Tumor specimens showed highly significant and large fold change differential expression of the levels of 39 miRNAs including miR-135b, miR-96, miR-182, miR-183, miR-1, and miR-133a, relative to normal colon tissue. Significant differences were also seen in 6 miRNAs including miR-31 and miR-592, in the direct comparison of tumors that were deficient or proficient for mismatch repair. Examination of the genomic regions containing differentially expressed miRNAs revealed that they were also differentially methylated in colon cancer at a far greater rate than would be expected by chance. A network of interactions between these miRNAs and genes associated with colon cancer provided evidence for the role of these miRNAs as oncogenes by attenuation of tumor suppressor genes. Conclusion: Colon tumors show differential expression of miRNAs depending on mismatch repair status. miRNA expression in colon tumors has an epigenetic component and altered expression that may reflect a reversion to regulatory programs characteristic of undifferentiated proliferative developmental states.

Original languageEnglish (US)
Article number401
JournalBMC Cancer
Volume9
DOIs
StatePublished - Nov 18 2009

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DNA Mismatch Repair
MicroRNAs
Colonic Neoplasms
Neoplasms
Colon
Epigenomics
Small Untranslated RNA
Tumor Suppressor Genes
Oncogenes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Genetics

Cite this

Human colon cancer profiles show differential microRNA expression depending on mismatch repair status and are characteristic of undifferentiated proliferative states. / Sarver, Aaron L.; French, Amy J.; Borralho, Pedro M.; Thayanithy, Venugopal; Oberg, Ann L; Silverstein, Kevin A T; Morlan, Bruce W.; Riska, Shaun M.; Boardman, Lisa Allyn; Cunningham, Julie M; Subramanian, Subbaya; Wang, Liang; Smyrk, Thomas Christopher; Rodrigues, Cecilia M P; Thibodeau, Stephen N; Steer, Clifford J.

In: BMC Cancer, Vol. 9, 401, 18.11.2009.

Research output: Contribution to journalArticle

Sarver, AL, French, AJ, Borralho, PM, Thayanithy, V, Oberg, AL, Silverstein, KAT, Morlan, BW, Riska, SM, Boardman, LA, Cunningham, JM, Subramanian, S, Wang, L, Smyrk, TC, Rodrigues, CMP, Thibodeau, SN & Steer, CJ 2009, 'Human colon cancer profiles show differential microRNA expression depending on mismatch repair status and are characteristic of undifferentiated proliferative states', BMC Cancer, vol. 9, 401. https://doi.org/10.1186/1471-2407-9-401
Sarver, Aaron L. ; French, Amy J. ; Borralho, Pedro M. ; Thayanithy, Venugopal ; Oberg, Ann L ; Silverstein, Kevin A T ; Morlan, Bruce W. ; Riska, Shaun M. ; Boardman, Lisa Allyn ; Cunningham, Julie M ; Subramanian, Subbaya ; Wang, Liang ; Smyrk, Thomas Christopher ; Rodrigues, Cecilia M P ; Thibodeau, Stephen N ; Steer, Clifford J. / Human colon cancer profiles show differential microRNA expression depending on mismatch repair status and are characteristic of undifferentiated proliferative states. In: BMC Cancer. 2009 ; Vol. 9.
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abstract = "Background: Colon cancer arises from the accumulation of multiple genetic and epigenetic alterations to normal colonic tissue. microRNAs (miRNAs) are small, non-coding regulatory RNAs that post-transcriptionally regulate gene expression. Differential miRNA expression in cancer versus normal tissue is a common event and may be pivotal for tumor onset and progression. Methods: To identify miRNAs that are differentially expressed in tumors and tumor subtypes, we carried out highly sensitive expression profiling of 735 miRNAs on samples obtained from a statistically powerful set of tumors (n = 80) and normal colon tissue (n = 28) and validated a subset of this data by qRT-PCR. Results: Tumor specimens showed highly significant and large fold change differential expression of the levels of 39 miRNAs including miR-135b, miR-96, miR-182, miR-183, miR-1, and miR-133a, relative to normal colon tissue. Significant differences were also seen in 6 miRNAs including miR-31 and miR-592, in the direct comparison of tumors that were deficient or proficient for mismatch repair. Examination of the genomic regions containing differentially expressed miRNAs revealed that they were also differentially methylated in colon cancer at a far greater rate than would be expected by chance. A network of interactions between these miRNAs and genes associated with colon cancer provided evidence for the role of these miRNAs as oncogenes by attenuation of tumor suppressor genes. Conclusion: Colon tumors show differential expression of miRNAs depending on mismatch repair status. miRNA expression in colon tumors has an epigenetic component and altered expression that may reflect a reversion to regulatory programs characteristic of undifferentiated proliferative developmental states.",
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AU - Sarver, Aaron L.

AU - French, Amy J.

AU - Borralho, Pedro M.

AU - Thayanithy, Venugopal

AU - Oberg, Ann L

AU - Silverstein, Kevin A T

AU - Morlan, Bruce W.

AU - Riska, Shaun M.

AU - Boardman, Lisa Allyn

AU - Cunningham, Julie M

AU - Subramanian, Subbaya

AU - Wang, Liang

AU - Smyrk, Thomas Christopher

AU - Rodrigues, Cecilia M P

AU - Thibodeau, Stephen N

AU - Steer, Clifford J.

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N2 - Background: Colon cancer arises from the accumulation of multiple genetic and epigenetic alterations to normal colonic tissue. microRNAs (miRNAs) are small, non-coding regulatory RNAs that post-transcriptionally regulate gene expression. Differential miRNA expression in cancer versus normal tissue is a common event and may be pivotal for tumor onset and progression. Methods: To identify miRNAs that are differentially expressed in tumors and tumor subtypes, we carried out highly sensitive expression profiling of 735 miRNAs on samples obtained from a statistically powerful set of tumors (n = 80) and normal colon tissue (n = 28) and validated a subset of this data by qRT-PCR. Results: Tumor specimens showed highly significant and large fold change differential expression of the levels of 39 miRNAs including miR-135b, miR-96, miR-182, miR-183, miR-1, and miR-133a, relative to normal colon tissue. Significant differences were also seen in 6 miRNAs including miR-31 and miR-592, in the direct comparison of tumors that were deficient or proficient for mismatch repair. Examination of the genomic regions containing differentially expressed miRNAs revealed that they were also differentially methylated in colon cancer at a far greater rate than would be expected by chance. A network of interactions between these miRNAs and genes associated with colon cancer provided evidence for the role of these miRNAs as oncogenes by attenuation of tumor suppressor genes. Conclusion: Colon tumors show differential expression of miRNAs depending on mismatch repair status. miRNA expression in colon tumors has an epigenetic component and altered expression that may reflect a reversion to regulatory programs characteristic of undifferentiated proliferative developmental states.

AB - Background: Colon cancer arises from the accumulation of multiple genetic and epigenetic alterations to normal colonic tissue. microRNAs (miRNAs) are small, non-coding regulatory RNAs that post-transcriptionally regulate gene expression. Differential miRNA expression in cancer versus normal tissue is a common event and may be pivotal for tumor onset and progression. Methods: To identify miRNAs that are differentially expressed in tumors and tumor subtypes, we carried out highly sensitive expression profiling of 735 miRNAs on samples obtained from a statistically powerful set of tumors (n = 80) and normal colon tissue (n = 28) and validated a subset of this data by qRT-PCR. Results: Tumor specimens showed highly significant and large fold change differential expression of the levels of 39 miRNAs including miR-135b, miR-96, miR-182, miR-183, miR-1, and miR-133a, relative to normal colon tissue. Significant differences were also seen in 6 miRNAs including miR-31 and miR-592, in the direct comparison of tumors that were deficient or proficient for mismatch repair. Examination of the genomic regions containing differentially expressed miRNAs revealed that they were also differentially methylated in colon cancer at a far greater rate than would be expected by chance. A network of interactions between these miRNAs and genes associated with colon cancer provided evidence for the role of these miRNAs as oncogenes by attenuation of tumor suppressor genes. Conclusion: Colon tumors show differential expression of miRNAs depending on mismatch repair status. miRNA expression in colon tumors has an epigenetic component and altered expression that may reflect a reversion to regulatory programs characteristic of undifferentiated proliferative developmental states.

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