Abstract
Colorectal cancer is characterized by well-known genetic defects and approximately 50% of cases harbor oncogenic Ras mutations. Increased expression of Notch ligand Jagged1 occurs in several human malignancies, including colorectal cancer, and correlates with cancer progression, poor prognosis, and recurrence. Herein, we demonstrated that Jagged1 was constitutively processed in colorectal cancer tumors with mutant Kras, which ultimately triggered intrinsic reverse signaling via its nuclear-targeted intracellular domain Jag1-ICD. This process occurred when Kras/Erk/ADAM17 signaling was switched on, demonstrating that Jagged1 is a novel target of the Kras signaling pathway. Notably, Jag1-ICD promoted tumor growth and epithelial-mesenchymal transition, enhancing colorectal cancer progression and chemoresistance both in vitro and in vivo. These data highlight a novel role for Jagged1 in colorectal cancer tumor biology that may go beyond its effect on canonical Notch activation and suggest that Jag1-ICD may behave as an oncogenic driver that is able to sustain tumor pathogenesis and to confer chemoresistance through a noncanonical mechanism. SIGNIFICANCE: These findings present a novel role of the transcriptionally active Jag1-ICD fragment to confer and mediate some of the activity of oncogenic KRAS.
Highlights
Sporadic colorectal cancer development is characterized by well-known histopathological changes, resulting from specific genetic defects in selected oncogenes and tumor-suppressor genes
On the basis of the observation that Jagged1 transcripts are overexpressed in a large number of human colorectal cancers, while they are undetectable in the adjacent normal tissue [41, 42], we monitored the expression of Jagged1 transcripts in several human colorectal cancer cell lines by qRT-PCR assays
The Notch ligand Jagged1 is upregulated in a large number of cancers, where it plays a key role in cell growth, epithelial–mesenchymal transition (EMT) and metastatic process [10]
Summary
Sporadic colorectal cancer development is characterized by well-known histopathological changes, resulting from specific genetic defects in selected oncogenes and tumor-suppressor genes. The most of sporadic colorectal cancers and hereditary colorectal tumors show loss of APC function, the negative regulator of Wnt signaling, leading to abnormal. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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