CARF enrichment promotes epithelial-mesenchymal transition via Wnt/β-catenin signaling: Its clinical relevance and potential as a therapeutic target

Rajkumar S. Kalra, Anupama Chaudhary, A. Rum Yoon, Priyanshu Bhargava, Amr Omar, Sukant Garg, Chae Ok Yun, Sunil C. Kaul, Renu Wadhwa

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

CARF (Collaborator of ARF)/CDKN2AIP was discovered as a novel ARF-binding protein. It has been established as an essential cell survival, p53-, and cell proliferation-regulatory protein. Although a moderate upregulation of CARF caused growth arrest and senescence, its excessively enriched levels were shown to facilitate aggressive proliferation and malignant transformation of cancer cells. Here, we examined the relevance of CARF levels in clinical tumors and found its amplification (both at gene and transcript levels) in a variety of invasive and metastatic malignancies. Consistent with the clinical readouts, enrichment of CARF in cancer cells promoted epithelial-mesenchymal transition (EMT). Cancer database and molecular analyses revealed that it activates Wnt/β-catenin signaling axis, as evident by enhanced nuclear localization and function of β-catenin marked by increased level of SNAIL1, SNAIL2, ZEB1, and TWIST1 and its downstream gene targets. Of note, targeted knockdown of CARF led to decrease in nuclear β-catenin and its key downstream effectors, involved in EMT progression. Consistent with this, CARF targeting in vivo either by naked siRNA or CARF shRNA harboring adeno-oncolytic virus caused suppression of tumor progression and lung metastasis. Taken together, we report clinical and therapeutic relevance of CARF in EMT and cancer invasiveness/metastasis, and propose it as a potent therapeutic target of aggressive cancers.

Original languageEnglish
Article number39
JournalOncogenesis
Volume7
Issue number5
DOIs
StatePublished - 2018 May 1

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Catenins
Epithelial-Mesenchymal Transition
Neoplasms
Therapeutics
Small Interfering RNA
Chemical Databases
Oncolytic Viruses
Neoplasm Metastasis
Genes
Cell Survival
Carrier Proteins
Up-Regulation
Cell Proliferation
Lung
Growth

Cite this

Kalra, Rajkumar S. ; Chaudhary, Anupama ; Yoon, A. Rum ; Bhargava, Priyanshu ; Omar, Amr ; Garg, Sukant ; Yun, Chae Ok ; Kaul, Sunil C. ; Wadhwa, Renu. / CARF enrichment promotes epithelial-mesenchymal transition via Wnt/β-catenin signaling : Its clinical relevance and potential as a therapeutic target. In: Oncogenesis. 2018 ; Vol. 7, No. 5.
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CARF enrichment promotes epithelial-mesenchymal transition via Wnt/β-catenin signaling : Its clinical relevance and potential as a therapeutic target. / Kalra, Rajkumar S.; Chaudhary, Anupama; Yoon, A. Rum; Bhargava, Priyanshu; Omar, Amr; Garg, Sukant; Yun, Chae Ok; Kaul, Sunil C.; Wadhwa, Renu.

In: Oncogenesis, Vol. 7, No. 5, 39, 01.05.2018.

Research output: Contribution to journalArticle

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T1 - CARF enrichment promotes epithelial-mesenchymal transition via Wnt/β-catenin signaling

T2 - Its clinical relevance and potential as a therapeutic target

AU - Kalra, Rajkumar S.

AU - Chaudhary, Anupama

AU - Yoon, A. Rum

AU - Bhargava, Priyanshu

AU - Omar, Amr

AU - Garg, Sukant

AU - Yun, Chae Ok

AU - Kaul, Sunil C.

AU - Wadhwa, Renu

PY - 2018/5/1

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