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Smad7 Sustains Stat3 Expression and Signaling in Colon Cancer Cells

Claudia Maresca1, Giulia Di Maggio1, Carmine Stolfi1

  • 1Department of Systems Medicine, University of "Tor Vergata", 00133 Rome, Italy.

Cancers
|October 27, 2022
PubMed

Insights

Smad7 sustains signal transducer and activator of transcription (Stat)3 expression and activation in colorectal cancer (CRC) cells. This study reveals Smad7 directly regulates Stat3, impacting CRC cell proliferation and survival.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Colorectal cancer (CRC) cells exhibit heightened Signal Transducer and Activator of Transcription (Stat)3 activity, promoting proliferation and inhibiting apoptosis.
  • Mechanisms amplifying Stat3 activation in CRC remain incompletely understood.

Purpose of the Study:

  • To investigate whether Smad7, a Transforming Growth Factor-beta1 (TGF-β1) inhibitor, maintains Stat3 expression and activation in CRC cells.
  • To elucidate the regulatory relationship between Smad7 and Stat3 in the context of colorectal cancer.

Main Methods:

  • Comparative analysis of Smad7 and phosphorylated (p)/activated-Stat3 expression in CRC tissues versus adjacent normal mucosa.
  • Smad7 knockdown using antisense oligonucleotides (AS) in CRC cell lines (DLD-1, HCT116).
  • Assessment of downstream Stat3 targets (BCL-xL, survivin) and Stat3 RNA/protein levels post-Smad7 knockdown.
  • Chromatin immunoprecipitation (ChIP) assay to evaluate Smad7's direct effect on the Stat3 promoter.
  • Analysis of RNA-sequencing data from the Tumor, Normal, and Metastatic (TNM) plot database.

Main Results:

  • Smad7 and p-Stat3 were co-localized and upregulated in tumoral CRC areas compared to normal mucosa.
  • Smad7 knockdown significantly reduced p-Stat3 levels in both unstimulated and cytokine-stimulated CRC cells.
  • Reduced expression of Stat3 downstream targets, BCL-xL and survivin, was observed following Smad7 knockdown.
  • Smad7 knockdown led to decreased Stat3 RNA and protein expression.
  • ChIP assays confirmed Smad7 directly regulates the Stat3 promoter.
  • A positive correlation between Smad7 and Stat3 expression was identified in 1450 CRC samples from the TNM database.

Conclusions:

  • Smad7 positively regulates Stat3 expression and activation in colorectal cancer cells.
  • This study provides the first evidence of Smad7's direct regulatory role on Stat3 function in CRC.
  • Targeting the Smad7-Stat3 axis may represent a novel therapeutic strategy for colorectal cancer.
Keywords:
Smadcolonic neoplasiacytokinestranscription factors

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