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Apoptosis01:30

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Apoptosis is a combination of two Greek words, 'apo' and 'ptosis,' meaning separation and falling off, respectively. Hippocrates used this word to describe gangrene, which was caused due to bandaging of fractured bones. Apoptosis was distinguished from necrosis in 1970 when John Kerr reported observations of morphological changes occurring during apoptosis. During one experiment, he observed that the disruption of blood supply to the liver tissue resulted in a size...
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Activation of Apoptosis by Cytoplasmic Microinjection of Cytochrome c
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TGFβ-induced SMAD4-dependent Apoptosis Proceeded by EMT in CRC.

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Colorectal cancer in Saudi Arabia is aggressive. This study reveals Smad4 alterations link to poor prognosis and that TGFβ/Smad4 signaling drives epithelial-to-mesenchymal transition (EMT) and apoptosis in cancer cells.

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Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Colorectal cancer (CRC) is a major global health concern.
  • CRC in Saudi Arabia presents aggressively and at younger ages, necessitating novel therapeutic strategies.
  • The TGFβ/Smad4 signaling pathway is implicated in CRC initiation and progression.

Purpose of the Study:

  • To investigate the role of the TGFβ/Smad4 pathway in a large Saudi CRC patient cohort.
  • To elucidate the dual function of TGFβ in inducing epithelial-to-mesenchymal transition (EMT) and apoptosis.
  • To identify potential therapeutic targets within this pathway.

Main Methods:

  • Analysis of a large cohort of Saudi colorectal cancer patients.
  • In vitro studies using colorectal cancer cell lines.
  • Assessment of Smad4 alterations and protein expression.
  • Evaluation of TGFβ-induced EMT and apoptosis.
  • Investigation of key transcription factors (Snail1, Zeb1, KLF5, Sox4).

Main Results:

  • High frequency of Smad4 alterations and low Smad4 protein expression were observed, correlating with aggressive CRC and poor prognosis.
  • TGFβ induces Smad4-dependent EMT, followed by apoptosis in colorectal cancer cells.
  • Mesenchymal transcription factors Snail1 and Zeb1 are crucial for TGFβ-induced apoptosis.
  • KLF5 acts as an oncogene in CRC, and its inhibition is necessary for TGFβ-induced apoptosis.
  • TGFβ/Smad4 signaling inhibits KLF5 transcription, converting Sox4 from a tumor promoter to a suppressor.

Conclusions:

  • Smad4 alterations represent an independent marker for poor prognosis in Saudi colorectal cancer patients.
  • TGFβ/Smad4 signaling orchestrates a complex process involving EMT and subsequent apoptosis in colorectal cancer.
  • Targeting KLF5 may be a viable therapeutic strategy for aggressive colorectal cancer.