Liver Cancer Initiation Requires p53 Inhibition by CD44-Enhanced Growth Factor Signaling

Dhar, Debanjan; Antonucci, Laura; Nakagawa, Hayato; Kim, Ju Youn; Glitzner, Elisabeth; Caruso, Stefano; Shalapour, Shabnam; Yang, Ling; Valasek, Mark A.; Lee, Sooyeon; Minnich, Kerstin; Seki, Ekihiro; Tuckermann, Jan; Sibilia, Maria; Zucman‐Rossi, Jessica; Karin, Michael

doi:10.1016/j.ccell.2018.05.003

Cited by 162 publications

(153 citation statements)

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“…p53 increases the activation of p21 transcription, thereby facilitating cellular senescence . As a putative candidate for cancer treatment, p53/p21 signaling exerts a potent effect on senescence in various digestive system tumors, including HCC, colorectal cancer, gastric cancer and pancreatic cancer …”

Section: Introductionmentioning

confidence: 99%

circLARP4 induces cellular senescence through regulating miR‐761/RUNX3/p53/p21 signaling in hepatocellular carcinoma

Chen

Zuo

et al. 2019

Cancer Science

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Circular RNAs (circRNAs), a novel class of non‐coding RNAs, have emerged as indispensable modulators in human malignancies. Aberrant cellular senescence is a phenotype observed in various cancers. The association of circRNAs with cellular senescence in tumors is yet to determined. Here, we investigated the role of circLARP4 in cellular senescence and cell proliferation in hepatocellular carcinoma (HCC). Downregulated circLARP4 level was observed in HCC tissues and cell lines. Low expression level of circLARP4 independently predicted poor survival outcome. Gain‐of‐function and loss‐of‐function assays demonstrated that circLARP4 suppressed HCC cell proliferation, mediated cell cycle arrest and induced senescence in vitro. Levels of p53 and p21, 2 key regulatory molecules in cellular senescence, were increased in circLARP4‐overexpressed HCC cells and decreased in circLARP4‐silenced HCC cells. In vivo experiments further confirmed the tumor‐suppressing activity of circLARP4. Further mechanistic studies showed that circLARP4 dampened HCC progression by sponging miR‐761, thereby promoting the expression level of RUNX3 and activating the downstream p53/p21 signaling. Our study revealed the role of circLARP4/miR‐761/RUNX3/p53/p21 signaling in HCC progression, providing a potential survival predictor and therapeutic candidate for HCC.

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Section: Introductionmentioning

confidence: 99%

circLARP4 induces cellular senescence through regulating miR‐761/RUNX3/p53/p21 signaling in hepatocellular carcinoma

Chen

Zuo

et al. 2019

Cancer Science

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“…In cells lacking p53 function, de-repression of CD44 led to the survival of tumor growth, anti-apoptotic and mitogenic effects 57 . In hepatocellular carcinoma, CD44 was shown to induce AKT activation, which in turn resulted in phosphorylation and translocation of Mdm2, a negative regulator of p53, to the nucleus, terminating the p53 response 58 . High CD44 expression can promote growth and survival in different stages of tumor progression by counteracting p53 tumor-suppressor function while p53 acts to repress CD44 expression to promote its apoptotic and antiproliferative activities 57,58 .…”

mentioning

confidence: 99%

IGFBP-3 Blocks Hyaluronan-CD44 Signaling, Leading to Increased Acetylcholinesterase Levels in A549 Cell Media and Apoptosis in a p53-Dependent Manner

Price

Muterspaugh

Clegg

et al. 2020

Sci Rep

105

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Insulin-like growth factor binding protein-3 (IGFBP-3) belongs to a family of six IGF binding proteins. We previously found that IGFBP-3 exerts its cytotoxic effects on A549 (p53 wild-type) cell survival through a mechanism that depends on hyaluronan-CD44 interactions. To shed light on the mechanism employed, we used CD44-negative normal human lung cells (HFL1), A549, and H1299 (p53-null) lung cancer cells. A synthetic IGFBP-3 peptide ( 215 -KKGfYKKKQcRpSKGRKR-232 ) but not the mutant (K228AR230A), was able to bind hyaluronan more efficiently than the analogous sequences from the other IGFBPs. In a manner comparable to that of the IGFBP-3 protein, the peptide blocked hyaluronan-CD44 signaling, and more effectively inhibited viability of A549 cells than viability of either H1299 or HFL1 cell lines. Treatment with the IGFBP-3 protein or its peptide resulted in increased acetylcholinesterase concentration and activity in the A549 cell media but not in the media of either HFL1 or H1299, an effect that correlated with increased apoptosis and decreased cell viability. These effects were diminished upon the same treatment of A549 cells transfected with either p53 siRNA or acetylcholinesterase siRNA. Taken together, our results show that IGFBP-3 or its peptide blocks hyaluronan-CD44 signaling via a mechanism that depends on both p53 and acetylcholinesterase.Lung cancer is a devastating human disease and among the most common causes of cancer deaths worldwide 1,2 . Of all cases of the disease, non-small cell lung cancer (NSCLC) accounts for approximately 85% 3 .CD44 is a type 1 transmembrane cell-surface glycoprotein with tumor promoting functions in many types of cancer cells 4-7 . It is the main cell surface receptor for hyaluronan (HA) 5-9 . Found on the extracellular side of the cell membrane is the CD44 globular HA-binding domain (HABD) 9,10 shown previously to bind HA as a globular water-soluble protein 11 . CD44 is encoded by a single gene 5,6,12 and many different variant isoforms (CD44v) are generated by alternative splicing that yield different patterns of amino acid insertion into the stalk domain of CD44 with the smallest being the standard CD44 (CD44s) 5,13-15 . Residues 32-123 in the N-terminal domain of CD44, common to both CD44s and CD44v isoforms, contain the HA-binding motif 16 . Assessment of CD44 expression in human lung cancer cell lines 17 , including A549 and H1299 used in this study, showed that the predominant isoform expressed is CD44s 18 . Being a common marker for tumor-initiating cells/cancer stem cells in human carcinomas, CD44 has gained much attention in the cancer literature 14 . HA-CD44 binding is known to modulate numerous downstream signaling cascades, such as the ERK1/2/MAPK and PI3K/Akt pathways, leading to tumor cell proliferation, survival, chemoresistance, and invasiveness 5,7,12,19 .HA is a non-sulfated, anionic glycosaminoglycan 5,16,20,21 polymer composed of the disaccharide sequence (D-glucuronic acid and D-N-acetylglucosamine) without known post-synthetic modification 6,22-24 ...

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“…A signaling pathway that plays an essential role in promoting breast cancer aggressiveness (56). In addition, the activation of this STAT3 signaling pathway induce the expression of the stemness marker CD44 in hepatocellular carcinomas (60). Specifically, we demonstrate GPX8 regulation on IL6R that fails to activate the IL-6 trans-signaling.…”

Section: Discussionmentioning

confidence: 81%

Glutathione Peroxidase 8 (GPX8)-IL6 axis is essential in maintaining breast cancer mesenchymal stem-like state and aggressive phenotype

Khatib¹,

Balakrishnan²,

Ben-Yosef³

et al. 2019

Preprint

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Metabolic reprogramming as a downstream result of oncogenic signaling pathways has been described as a hallmark of cancer. Here, we describe a reverse scenario in which a metabolic enzyme regulates cancer cell behavior by triggering a signaling pathway. We find that glutathione peroxidase 8 (GPX8), a poorly characterized redox enzyme that resides in the endoplasmic reticulum, is upregulated during the epithelial-to-mesenchymal (EMT) program in HMLE and A549 cells. In cancer patients, high tumor levels of GPX8 correlate with mesenchymal markers and poor patient outcome. Strikingly, GPX8 knockout in mesenchymallike cells results in an epithelial-like morphology, downregulation of EMT characteristics, loss of cancer stemness features, and impeded tumor initiation in mice. We determine the mechanism governing this reduction in cancer aggressiveness is through the repression of crucial autocrine factors, in particular, interleukin-6 (IL-6). Specifically, GPX8 knockout impairs IL-6-driven activation of the JAK-STAT3 signaling pathway, a critical regulator of a cancer-aggressive state. Altogether, we uncover the GPX8-IL-6 axis as a novel metabolicinflammatory pathway that acts as a robust EMT activator and program to induce aggressive cancer cell characteristics.

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Liver Cancer Initiation Requires p53 Inhibition by CD44-Enhanced Growth Factor Signaling

Cited by 162 publications

References 65 publications

circLARP4 induces cellular senescence through regulating miR‐761/RUNX3/p53/p21 signaling in hepatocellular carcinoma

circLARP4 induces cellular senescence through regulating miR‐761/RUNX3/p53/p21 signaling in hepatocellular carcinoma

IGFBP-3 Blocks Hyaluronan-CD44 Signaling, Leading to Increased Acetylcholinesterase Levels in A549 Cell Media and Apoptosis in a p53-Dependent Manner

Glutathione Peroxidase 8 (GPX8)-IL6 axis is essential in maintaining breast cancer mesenchymal stem-like state and aggressive phenotype

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