Ras Stabilization Through Aberrant Activation of Wnt/β-Catenin Signaling Promotes Intestinal Tumorigenesis

Abstract

The transcription factor TCF7L1 is an embryonic stem cell signature gene that is upregulated in multiple aggressive cancer types, but its role in skin tumorigenesis has not yet been defined. Here we document TCF7L1 upregulation in skin squamous cell carcinoma (SCC) and demonstrate that TCF7L1 overexpression increases tumor incidence, tumor multiplicity, and malignant progression in the chemically induced mouse model of skin SCC. Additionally, we show that downregulation of TCF7L1 and its paralogue TCF7L2 reduces tumor growth in a xenograft model of human skin SCC. Using separation-of-function mutants, we show that TCF7L1 promotes tumor growth, enhances cell migration, and overrides oncogenic RAS-induced senescence independently of its interaction with b-catenin. Through transcriptome profiling and combined gain-and loss-of-function studies, we identified LCN2 as a major downstream effector of TCF7L1 that drives tumor growth. Our findings establish a tumor-promoting role for TCF7L1 in skin and elucidate the mechanisms underlying its tumorigenic capacity.

Transgenic expression of oncogenic BRAF induces loss of stem cells in the mouse intestine, which is antagonized by β-catenin activity

“…50 In contrast, activation of MAPK signaling downstream of oncogenic BRAF can inhibit β-catenin effects in melanoma. 51 Therefore, interactions between the two signaling cascades may be highly cell type-and context-specific.…”

K-ras Mutations as the Earliest Driving Force in a Subset of Colorectal Carcinomas

“…Therefore, it seems that MAPK activities (activated Ras protein included) are negatively regulated by the normal function of the APC protein, which degrades β-catenin, and is positively regulated by APC mutation or by the abundance of Wnt signaling, which increases cytoplasmic and nuclear levels of β-catenin. This regulation was indeed proved to be mediated by β-catenin (42,43). Thus, oncogenic K-ras protein augments its action in the context of Wnt/APC/β-catenin hyperactivation.…”

“…This effect is wider, since the inhibition of degradation of the oncogenic form of Ras protein by various components of Wnt/β-catenin pathway was also proved (42). Therefore, it seems that MAPK activities (activated Ras protein included) are negatively regulated by the normal function of the APC protein, which degrades β-catenin, and is positively regulated by APC mutation or by the abundance of Wnt signaling, which increases cytoplasmic and nuclear levels of β-catenin.…”

“…Nonetheless, this action is exerted only if Wnt signaling is active (45). Interestingly, GSK-3β is promoted via Wnt activation leading to Ras phosphorylation and Ras stabilization to RAS-GTP state, creating a vicious cycle (42). Second, LRP6 is phoshorylated by oncogenic K-ras signaling; P-LRP6 promotes canonical Wnt/β-catenin pathway and eliminates β-catenin in cell membrane, conferring to loss of cell-cell contact and epithelial-mesenchymal transition (47).…”

Ras Regulates SCFβ-TrCP Protein Activity and Specificity via Its Effector Protein NORE1A

“…An interesting dichotomy exists because Ras has been reported to exhibit both positive and negative effects on the pathway (4 -6). Moreover, although synergistic activation of transformation by Ras and Wnt/␤-catenin has been reported, other reports have identified an antagonistic role in transformation (5,6). How Ras impacts the Wnt/␤-catenin pathway is still not fully understood, nor is the balance of cellular factors that dictate whether a net positive or negative effect is observed for Ras on Wnt/␤-catenin pathway signaling.…”