Osteopontin—A Master Regulator of Epithelial-Mesenchymal Transition

Kothari, Anai N.; Arffa, Matthew; Chang, Victor; Blackwell, Robert H.; Syn, Wing–Kin; Zhang, Jiwang; Mi, Zhiyong; Kuo, Paul C.

doi:10.3390/jcm5040039

Cited by 96 publications

(110 citation statements)

References 118 publications

(125 reference statements)

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“…5C, left panel). Surprisingly, two other targets of β-catenin, osteopontin [OPN; which is known as a master regulator of EMT (41) via its ability to stabilize vimentin (42)] and Axin2 [AXIN2, which enhances EMT via induction of Snail (43)] were not suppressed, and instead were increased in Daple-YE cells (Fig. 5C, right panel).…”

Section: Resultsmentioning

confidence: 99%

Convergence of Wnt, growth factor, and heterotrimeric G protein signals on the guanine nucleotide exchange factor Daple

et al. 2018

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Cellular proliferation, differentiation, and morphogenesis are shaped by multiple signaling cascades; their concurrent dysregulation plays an integral role in cancer progression and is a common feature of many malignancies. Three such cascades that contribute to the oncogenic potential are those mediated by Wnt and Frizzled (FZD), growth factor receptor tyrosine kinases (RTKs), and trimeric G proteins and GPCRs. Daple is a Dishevelled (Dvl)- and FZD-binding protein and a guanine-nucleotide exchange factor (GEF) for the trimeric G protein, Gαi. Daple enhances β-catenin-independent Wnt signaling through its ability to activate the pathway downstream of the Wnt5/FZD7 pathway. Here we identified that Daple is a substrate of multiple RTKs and non-RTKs, and hence, a point of convergence for all three cascades. We show that phosphorylation by both RTKs and non-RTKs near the Dvl-binding motif in Daple dissociated Daple:Dvl complexes and augmented the ability of Daple to bind and activate Gαi which potentiated β-catenin-independent Wnt signals and triggered epithelial-mesenchymal transition (EMT) in a manner similar to that triggered by Wnt5A/FZD. Although Daple acts as a tumor suppressor in the healthy colon, but concurrent upregulation of Daple and epidermal growth factor receptor (EGFR) in colorectal tumors from patients was associated with poor prognosis. We conclude that Daple-dependent activation of Gαi and enhancement of β-catenin-independent Wnt signals is not just triggered by Wnt5a/FZD to suppress tumorigenesis, but also is hijacked by growth factor-RTKs to stoke tumor progression. Thus, this work defines a crosstalk paradigm amongst growth factor RTKs, trimeric G-proteins, and Wnt/FZD in cancer biology.

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Section: Resultsmentioning

confidence: 99%

Convergence of Wnt, growth factor, and heterotrimeric G protein signals on the guanine nucleotide exchange factor Daple

et al. 2018

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“…OPN is a secreted non-collagenous, matrix glycoprotein, implicated in the progression of fibrosis and cancer and an influential factor in the tumor microenvironment (35,36). In the liver, OPN has been shown to modulate regeneration, inflammation and fibrosis and more recently, to induce dedifferentiation of hepatocytes (37,38).…”

Section: Discussionmentioning

confidence: 99%

Circulating Osteopontin and Prediction of Hepatocellular Carcinoma Development in a Large European Population

Duarte‐Salles

Misra

Stępień

et al. 2016

Cancer Prevention Research

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We previously identified osteopontin (OPN) as a promising marker for the early detection of hepatocellular carcinoma (HCC). In this study, we investigated the association between pre-diagnostic circulating OPN levels and HCC incidence in a large population-based cohort. A nested-case control study was conducted within the EPIC cohort. During a mean follow-up of 4.8 years, 100 HCC cases were identified. Each case was matched to two controls and OPN levels were measured in baseline plasma samples. Viral hepatitis, liver function and alpha-fetoprotein (AFP) tests were also conducted. Conditional logistic regression models were used to calculate multivariable odds ratio (OR) and 95% confidence intervals (95%CI) for OPN levels in relation to HCC. Receiver operating characteristics curves were constructed to determine the discriminatory accuracy of OPN alone or in combination with other liver biomarkers in the prediction of HCC. OPN levels were positively associated with HCC risk (per 10% increment, ORmultivariable=1.30; 95%CI:1.14–1.48). The association was stronger among cases diagnosed within two years of follow-up. Adding liver function tests to OPN improved the discriminatory performance for subjects who developed HCC (AUC=0.86). For cases diagnosed within two years, the combination of OPN and AFP was best able to predict HCC risk (AUC=0.88). The best predictive model for HCC in this low-risk population is OPN in combination with liver function tests. Within two years of diagnosis, the combination of OPN and AFP best predicted HCC development, suggesting that measuring OPN and AFP could identify high-risk groups independently of a liver disease diagnosis.

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“…We found that constitutive phosphoactivation of Daple by Akt [mimicked by SD mutation] supresses several key canonical Wnt responsive β -catenin/TCF/LEF target genes (MYC, CCND1 and SFRP1;Figure 6J), consistent with its observed growth suppressive properties. Surprisingly, two other targets of β -catenin, osteopontin [OPN; which is known as a master regulator of EMT(Kothari et al, 2016) via its ability to stabilize vimentin(Dong et al, 2016)] and Axin2 [AXIN2, which enhances EMT via induction of Snail(Yook et al, 2006)] were not suppressed, and instead were increased in Daple-SD cells(Figure 6K), also consistent with its promigratory phenotype. Constitutive inactivation of the Akt→pS1428-Daple axis [as mimicked by SA and RC mutants] was associated with enhanced transcription of β catenin/TCF/LEF target genes (MYC and CCND1;Figure 6J) and suppression of key inducers of EMT (AXIN2 and VIM;Figure 6K); all consistent with the pro-growth and poorly motile phenotype of these cells.…”

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confidence: 75%