: 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.

Maresca, C., Di Maggio, G., Stolfi, C., Laudisi, F., Colella, M., Pacifico, T., et al. (2022). Smad7 Sustains Stat3 Expression and Signaling in Colon Cancer Cells. CANCERS, 14(20), 1-12 [10.3390/cancers14204993].

Smad7 Sustains Stat3 Expression and Signaling in Colon Cancer Cells

Sica, Giuseppe;Monteleone, Ivan;
2022-10-12

Abstract

: 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.
12-ott-2022
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore MED/18 - CHIRURGIA GENERALE
English
Smad
colonic neoplasia
cytokines
transcription factors
Maresca, C., Di Maggio, G., Stolfi, C., Laudisi, F., Colella, M., Pacifico, T., et al. (2022). Smad7 Sustains Stat3 Expression and Signaling in Colon Cancer Cells. CANCERS, 14(20), 1-12 [10.3390/cancers14204993].
Maresca, C; Di Maggio, G; Stolfi, C; Laudisi, F; Colella, M; Pacifico, T; Di Grazia, A; Di Fusco, D; Congiu, D; Guida, Am; Sica, G; Monteleone, I; Monteleone, G
Articolo su rivista
File in questo prodotto:
File Dimensione Formato  
Smad7.pdf

accesso aperto

Licenza: Creative commons
Dimensione 2.46 MB
Formato Adobe PDF
2.46 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/314659
Citazioni
  • ???jsp.display-item.citation.pmc??? 5
  • Scopus 8
  • ???jsp.display-item.citation.isi??? 5
social impact