DNA damage-induced ephrin-B2 reverse signaling promotes chemoresistance and drives EMT in colorectal carcinoma harboring mutant p53

Abstract

Mutation in the TP53 gene positively correlates with increased incidence of chemoresistance in different cancers. In this study, we investigated the mechanism of chemoresistance and epithelial-to-mesenchymal transition (EMT) in colorectal cancer involving the gain-of-function (GOF) mutant p53/ephrin-B2 signaling axis. Bioinformatic analysis of the NCI-60 data set and subsequent hub prediction identified EFNB2 as a possible GOF mutant p53 target gene, responsible for chemoresistance. We show that the mutant p53-NF-Y complex transcriptionally upregulates EFNB2 expression in response to DNA damage. Moreover, the acetylated form of mutant p53 protein is recruited on the EFNB2 promoter and positively regulates its expression in conjunction with coactivator p300. In vitro cell line and in vivo nude mice data show that EFNB2 silencing restores chemosensitivity in mutant p53-harboring tumors. In addition, we observed high expression of EFNB2 in patients having neoadjuvant non-responder colorectal carcinoma compared with those having responder version of the disease. In the course of deciphering the drug resistance mechanism, we also show that ephrin-B2 reverse signaling induces ABCG2 expression after drug treatment that involves JNK-c-Jun signaling in mutant p53 cells. Moreover, 5-fluorouracil-induced ephrin-B2 reverse signaling promotes tumorigenesis through the Src-ERK pathway, and drives EMT via the Src-FAK pathway. We thus conclude that targeting ephrin-B2 might enhance the therapeutic potential of DNA-damaging chemotherapeutic agents in mutant p53-bearing human tumors.

Upregulation of let‑7f‑5p promotes chemotherapeutic resistance in colorectal cancer by directly repressing several pro‑apoptotic proteins

“…Loss or mutation of the p53 gene has been identified to be positively associated with the recurrent incidence of chemotherapeutic resistance in different types of cancer (27). In CRC, p53 is mutated in ~50% of patients and these mutations of are considered to be inactivating, leaving to TP53 being incapable of regularly exerting its functions, including its pro-apoptotic role (28,29).…”

Scutellaria?barbata D. Don inhibits migration and invasion of colorectal cancer cells via suppression of PI3K/AKT and TGF‑β/Smad signaling pathways

“…Tumor metastasis is a complex process, and is highly regulated by multiple mechanisms, including aberrant activation of the phosphoinositide 3-kinase (PI3K)/AKT and transforming growth factor (TGF)-β/Smad pathways (8)(9)(10)(11). Furthermore, a large number of studies have shown that matrix metalloproteinase (MMP) overexpression is involved in numerous malignant tumors, including esophageal cancer, breast cancer, liver cancer and rectal cancer (12)(13)(14)(15)(16).…”

E2 Ubiquitin-conjugating Enzyme, UBE2C Gene, Is Reciprocally Regulated by Wild-type and Gain-of-Function Mutant p53

“…The growing description of biochemical and biological functions of mutant p53 shows that it not only loses the tumor-suppressive functions of its wildtype counterpart but also acquires novel oncogenic gain-offunction (GOF) properties (12). It has been previously demonstrated that mutant p53 interacts with the CCAAT-binding factor NF-Y, and this complex serves to up-regulate NF-Y target genes such as CCNA, CCNB, CDK1, CDC25C, and EFNB2 to promote cell cycle progression and chemoresistance following drug treatment (4,15). Surprisingly, wild-type p53 has been shown to interact with the same transcription factor NF-Y (16) and regulates many of the same target genes as described for mutant p53.…”