Smad7 Sustains Stat3 Expression and Signaling in Colon Cancer Cells
Colorectal cancer (CRC) cells contain elevated levels of active signal transducer and the activator of transcription (Stat)-3, which exerts proliferative and anti-apoptotic effects. Various molecules produced in the CRC tissue can activate Stat3, but the mechanisms that amplify such an activation ar...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-10-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/20/4993 |
| _version_ | 1797474551449255936 |
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| author | Claudia Maresca Giulia Di Maggio Carmine Stolfi Federica Laudisi Marco Colella Teresa Pacifico Antonio Di Grazia Davide Di Fusco Daniele Congiu Andrea Martina Guida Giuseppe Sica Ivan Monteleone Giovanni Monteleone |
| author_facet | Claudia Maresca Giulia Di Maggio Carmine Stolfi Federica Laudisi Marco Colella Teresa Pacifico Antonio Di Grazia Davide Di Fusco Daniele Congiu Andrea Martina Guida Giuseppe Sica Ivan Monteleone Giovanni Monteleone |
| author_sort | Claudia Maresca |
| collection | DOAJ |
| description | Colorectal cancer (CRC) cells contain elevated levels of active signal transducer and the activator of transcription (Stat)-3, which exerts proliferative and anti-apoptotic effects. Various molecules produced in the CRC tissue can activate Stat3, but the mechanisms that amplify such an activation are yet to be determined. In this paper, we assessed whether Smad7, an inhibitor of Transforiming Growth Factor (TGF)-β1 activity, sustains Stat3 expression/activation in CRC cells. Both Smad7 and phosphorylated (p)/activated-Stat3 were more expressed in the tumoral areas of CRC patients, compared to the normal adjacent colonic mucosa of the same patients, and were co-localized in primary CRC cells and CRC cell lines. The knockdown of Smad7 with a Smad7 antisense oligonucleotide (AS) reduced p-Stat3 in both unstimulated and interleukin (IL)-6- and IL-22-stimulated DLD-1 and HCT116 cells. Consistently, reduced levels of BCL-xL and survivin, two downstream signaling targets of Stat3 activation, were seen in Smad7 AS-treated cells. An analysis of the mechanisms underlying Smad7 AS-induced Stat3 inactivation revealed that Smad7 AS reduced Stat3 RNA and protein expression. A chromatin immunoprecipitation assay showed the direct regulatory effect of Smad7 on the Stat3 promoter. RNA-sequencing data from the Tumor, Normal and Metastatic (TNM) plot database showed a positive correlation between Smad7 and Stat3 in 1450 CRC samples. To our knowledge, this is the first evidence supporting the theory that Smad7 positively regulates Stat3 function in CRC. |
| first_indexed | 2024-03-09T20:31:44Z |
| format | Article |
| id | doaj.art-15665be14d3f41389c28d51508363455 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T20:31:44Z |
| publishDate | 2022-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-15665be14d3f41389c28d515083634552023-11-23T23:20:11ZengMDPI AGCancers2072-66942022-10-011420499310.3390/cancers14204993Smad7 Sustains Stat3 Expression and Signaling in Colon Cancer CellsClaudia Maresca0Giulia Di Maggio1Carmine Stolfi2Federica Laudisi3Marco Colella4Teresa Pacifico5Antonio Di Grazia6Davide Di Fusco7Daniele Congiu8Andrea Martina Guida9Giuseppe Sica10Ivan Monteleone11Giovanni Monteleone12Department of Systems Medicine, University of “Tor Vergata”, 00133 Rome, ItalyDepartment of Systems Medicine, University of “Tor Vergata”, 00133 Rome, ItalyDepartment of Systems Medicine, University of “Tor Vergata”, 00133 Rome, ItalyDepartment of Systems Medicine, University of “Tor Vergata”, 00133 Rome, ItalyDepartment of Systems Medicine, University of “Tor Vergata”, 00133 Rome, ItalyDepartment of Systems Medicine, University of “Tor Vergata”, 00133 Rome, ItalyDepartment of Systems Medicine, University of “Tor Vergata”, 00133 Rome, ItalyDepartment of Systems Medicine, University of “Tor Vergata”, 00133 Rome, ItalyDepartment of Systems Medicine, University of “Tor Vergata”, 00133 Rome, ItalyDepartment of Surgery, University of “Tor Vergata”, 00133 Rome, ItalyDepartment of Surgery, University of “Tor Vergata”, 00133 Rome, ItalyDepartment of Systems Medicine, University of “Tor Vergata”, 00133 Rome, ItalyDepartment of Systems Medicine, University of “Tor Vergata”, 00133 Rome, ItalyColorectal cancer (CRC) cells contain elevated levels of active signal transducer and the activator of transcription (Stat)-3, which exerts proliferative and anti-apoptotic effects. Various molecules produced in the CRC tissue can activate Stat3, but the mechanisms that amplify such an activation are yet to be determined. In this paper, we assessed whether Smad7, an inhibitor of Transforiming Growth Factor (TGF)-β1 activity, sustains Stat3 expression/activation in CRC cells. Both Smad7 and phosphorylated (p)/activated-Stat3 were more expressed in the tumoral areas of CRC patients, compared to the normal adjacent colonic mucosa of the same patients, and were co-localized in primary CRC cells and CRC cell lines. The knockdown of Smad7 with a Smad7 antisense oligonucleotide (AS) reduced p-Stat3 in both unstimulated and interleukin (IL)-6- and IL-22-stimulated DLD-1 and HCT116 cells. Consistently, reduced levels of BCL-xL and survivin, two downstream signaling targets of Stat3 activation, were seen in Smad7 AS-treated cells. An analysis of the mechanisms underlying Smad7 AS-induced Stat3 inactivation revealed that Smad7 AS reduced Stat3 RNA and protein expression. A chromatin immunoprecipitation assay showed the direct regulatory effect of Smad7 on the Stat3 promoter. RNA-sequencing data from the Tumor, Normal and Metastatic (TNM) plot database showed a positive correlation between Smad7 and Stat3 in 1450 CRC samples. To our knowledge, this is the first evidence supporting the theory that Smad7 positively regulates Stat3 function in CRC.https://www.mdpi.com/2072-6694/14/20/4993colonic neoplasiaSmadtranscription factorscytokines |
| spellingShingle | Claudia Maresca Giulia Di Maggio Carmine Stolfi Federica Laudisi Marco Colella Teresa Pacifico Antonio Di Grazia Davide Di Fusco Daniele Congiu Andrea Martina Guida Giuseppe Sica Ivan Monteleone Giovanni Monteleone Smad7 Sustains Stat3 Expression and Signaling in Colon Cancer Cells Cancers colonic neoplasia Smad transcription factors cytokines |
| title | Smad7 Sustains Stat3 Expression and Signaling in Colon Cancer Cells |
| title_full | Smad7 Sustains Stat3 Expression and Signaling in Colon Cancer Cells |
| title_fullStr | Smad7 Sustains Stat3 Expression and Signaling in Colon Cancer Cells |
| title_full_unstemmed | Smad7 Sustains Stat3 Expression and Signaling in Colon Cancer Cells |
| title_short | Smad7 Sustains Stat3 Expression and Signaling in Colon Cancer Cells |
| title_sort | smad7 sustains stat3 expression and signaling in colon cancer cells |
| topic | colonic neoplasia Smad transcription factors cytokines |
| url | https://www.mdpi.com/2072-6694/14/20/4993 |
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