Abstract
The relationship between therapeutic response and modifications of microRNA (miRNA) transcriptome in colorectal cancer (CRC) remains unknown. We investigated this issue by profiling the expression of 667 miRNAs in 2 human CRC cell lines, one sensitive and the other resistant to cetuximab (Caco-2 and HCT-116, respectively), through TaqMan real-time PCR. Caco-2 and HCT-116 expressed different sets of miRNAs after treatment. Specifically, 21 and 22 miRNAs were differentially expressed in Caco-2 or HCT-116, respectively (t test, P ≤ 0.01). By testing the expression of differentially expressed miRNAs in CRC patients, we found that miR-146b-3p and miR-486-5p are more abundant in K-ras-mutated samples with respect to wild-type ones (Wilcoxon test, P ≤ 0.05). Sixty-seven percent of differentially expressed miRNAs were involved in cancer, including CRC, whereas 19 miRNA targets had been previously reported to be involved in the cetuximab pathway and CRC. We identified 25 transcription factors putatively controlling these miRNAs, 11 of which have been already reported to be involved in CRC. On the basis of these data, we suggest that the downregulation of let-7b and let-7e (targeting K-ras) and the upregulation of miR-17* (a CRC marker) could be considered as candidate molecular markers of cetuximab resistance. Global network functional analysis (based on miRNA targets) showed a significant overrepresentation of cancer-related biological processes and networks centered on critical nodes involved in epidermal growth factor receptor internalization and ubiquitin-mediated degradation. The identification of miRNAs, whose expression is linked to the efficacy of therapy, should allow the ability to predict the response of patients to treatment and possibly lead to a better understanding of the molecular mechanisms of drug response.
| Original language | English |
|---|---|
| Pages (from-to) | 3396-3409 |
| Number of pages | 14 |
| Journal | Molecular Cancer Therapeutics |
| Volume | 9 |
| Issue number | 12 |
| DOIs | |
| Publication status | Published - Dec 2010 |
Fingerprint
ASJC Scopus subject areas
- Oncology
- Cancer Research
Cite this
Specific alterations of microRNA transcriptome and global network structure in colorectal carcinoma after cetuximab treatment. / Ragusa, Marco; Majorana, Alessandra; Statello, Luisa; Maugeri, Marco; Salito, Loredana; Barbagallo, Davide; Guglielmino, Maria Rosa; Duro, Laura R.; Angelica, Rosario; Caltabiano, Rosario; Biondi, Antonio; Di Vita, Maria; Privitera, Giuseppe; Scalia, Marina; Cappellani, Alessandro; Vasquez, Enrico; Lanzafame, Salvatore; Basile, Francesco; Di Pietro, Cinzia; Purrello, Michele.
In: Molecular Cancer Therapeutics, Vol. 9, No. 12, 12.2010, p. 3396-3409.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Specific alterations of microRNA transcriptome and global network structure in colorectal carcinoma after cetuximab treatment
AU - Ragusa, Marco
AU - Majorana, Alessandra
AU - Statello, Luisa
AU - Maugeri, Marco
AU - Salito, Loredana
AU - Barbagallo, Davide
AU - Guglielmino, Maria Rosa
AU - Duro, Laura R.
AU - Angelica, Rosario
AU - Caltabiano, Rosario
AU - Biondi, Antonio
AU - Di Vita, Maria
AU - Privitera, Giuseppe
AU - Scalia, Marina
AU - Cappellani, Alessandro
AU - Vasquez, Enrico
AU - Lanzafame, Salvatore
AU - Basile, Francesco
AU - Di Pietro, Cinzia
AU - Purrello, Michele
PY - 2010/12
Y1 - 2010/12
N2 - The relationship between therapeutic response and modifications of microRNA (miRNA) transcriptome in colorectal cancer (CRC) remains unknown. We investigated this issue by profiling the expression of 667 miRNAs in 2 human CRC cell lines, one sensitive and the other resistant to cetuximab (Caco-2 and HCT-116, respectively), through TaqMan real-time PCR. Caco-2 and HCT-116 expressed different sets of miRNAs after treatment. Specifically, 21 and 22 miRNAs were differentially expressed in Caco-2 or HCT-116, respectively (t test, P ≤ 0.01). By testing the expression of differentially expressed miRNAs in CRC patients, we found that miR-146b-3p and miR-486-5p are more abundant in K-ras-mutated samples with respect to wild-type ones (Wilcoxon test, P ≤ 0.05). Sixty-seven percent of differentially expressed miRNAs were involved in cancer, including CRC, whereas 19 miRNA targets had been previously reported to be involved in the cetuximab pathway and CRC. We identified 25 transcription factors putatively controlling these miRNAs, 11 of which have been already reported to be involved in CRC. On the basis of these data, we suggest that the downregulation of let-7b and let-7e (targeting K-ras) and the upregulation of miR-17* (a CRC marker) could be considered as candidate molecular markers of cetuximab resistance. Global network functional analysis (based on miRNA targets) showed a significant overrepresentation of cancer-related biological processes and networks centered on critical nodes involved in epidermal growth factor receptor internalization and ubiquitin-mediated degradation. The identification of miRNAs, whose expression is linked to the efficacy of therapy, should allow the ability to predict the response of patients to treatment and possibly lead to a better understanding of the molecular mechanisms of drug response.
AB - The relationship between therapeutic response and modifications of microRNA (miRNA) transcriptome in colorectal cancer (CRC) remains unknown. We investigated this issue by profiling the expression of 667 miRNAs in 2 human CRC cell lines, one sensitive and the other resistant to cetuximab (Caco-2 and HCT-116, respectively), through TaqMan real-time PCR. Caco-2 and HCT-116 expressed different sets of miRNAs after treatment. Specifically, 21 and 22 miRNAs were differentially expressed in Caco-2 or HCT-116, respectively (t test, P ≤ 0.01). By testing the expression of differentially expressed miRNAs in CRC patients, we found that miR-146b-3p and miR-486-5p are more abundant in K-ras-mutated samples with respect to wild-type ones (Wilcoxon test, P ≤ 0.05). Sixty-seven percent of differentially expressed miRNAs were involved in cancer, including CRC, whereas 19 miRNA targets had been previously reported to be involved in the cetuximab pathway and CRC. We identified 25 transcription factors putatively controlling these miRNAs, 11 of which have been already reported to be involved in CRC. On the basis of these data, we suggest that the downregulation of let-7b and let-7e (targeting K-ras) and the upregulation of miR-17* (a CRC marker) could be considered as candidate molecular markers of cetuximab resistance. Global network functional analysis (based on miRNA targets) showed a significant overrepresentation of cancer-related biological processes and networks centered on critical nodes involved in epidermal growth factor receptor internalization and ubiquitin-mediated degradation. The identification of miRNAs, whose expression is linked to the efficacy of therapy, should allow the ability to predict the response of patients to treatment and possibly lead to a better understanding of the molecular mechanisms of drug response.
UR - http://www.scopus.com/inward/record.url?scp=78650505164&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=78650505164&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-10-0137
DO - 10.1158/1535-7163.MCT-10-0137
M3 - Article
C2 - 20881268
AN - SCOPUS:78650505164
VL - 9
SP - 3396
EP - 3409
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
SN - 1535-7163
IS - 12
ER -