Abstract
Overactivation of Ras signaling is very common in the hepatocellular carcinoma (HCC) due to its constitutive active mutation, which makes it a big challenge to target Ras signaling. Therefore, identifying effectors downstream of Ras signaling would benefit the development of novel therapeutic strategies. In this study, it was found that the expression of CARF (collaborate of ARF) was induced by oncogenic RasV12. The expression of CARF was up-regulated in both HCC mouse model (Alb-Cre; P53f/f; Loxp-Stop-Loxp-RasG12D) and human HCC clinical samples. Overexpression of CARF promoted the growth and migration of HCC cells, while knocking down the expression of CARF inhibited the growth and migration of HCC cells. In the mechanism study, CARF was found to interact with beta-catenin, impaired the interaction between beta-catenin and ICAT, and activated beta-catenin/TCF signaling. Moreover, knocking down the expression of CARF inhibited the tumorigenesis in the HCC mouse model. Taken together, this study revealed the oncogenic functions of CARF in the tumorigenesis of HCC by activating beta-catenin/TCF signaling, and suggested CARF might be a therapeutic target in the treatment of HCC.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world and its incidence is increasing yearly [1]
This study revealed the oncogenic functions of CARF in the tumorigenesis of hepatocellular carcinoma (HCC) by activating beta-catenin/TCF signaling, and suggested CARF might be a therapeutic target in the treatment of HCC
It was found that the mRNA level and protein level of CARF were increased in the HCC mouse model compared with their control littermates (P53f/f; L-S-L-RasG12D) (Figure 1B–1C)
Summary
Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world and its incidence is increasing yearly [1]. Surgical operation and chemotherapy have played the crucial roles in the treatment of HCC, the survival of HCC patients is still very poor. Better understanding the molecular mechanisms driven HCC would benefit the clinical treatment. Over-activation Ras signaling due to its constitutive mutation on the 12th code is frequently observed in HCC clinical samples [2]. Oncogenic Ras signaling promoted the growth, migration and malignant transformation of HCC cells. Recent studies have shown that oncogenic Ras signaling reprogrammed the metabolic profile of cancer cells [3], suggesting the pivotal roles of Ras in the progression of HCC. The development of small molecular inhibitors targeting Ras signaling is unsuccessful up to date. Identifying the effectors downstream of Ras would provide novel target
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