Osteopontin promotes epithelial-mesenchymal transition of hepatocellular carcinoma through regulating vimentin

Dong, Qiongzhu; Zhu, Xiaoye; Dai, Chun; Zhang, Xiaofei; Gao, Xiaomei; Wei, Jie; Sheng, Yuan‐Yuan; Zheng, Yan; Yu, Jian; Xie, Lu; Qin, Yi; Qiao, Peng; Zhou, Chen; Yu, Xinxin; Jia, Hongyan; Ren, Ning; Zhou, Haijun; Ye, Qing–Hai; Qin, Lun–Xiu

doi:10.18632/oncotarget.7016

Cited by 62 publications

(64 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 99%

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

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Accumulating evidence has demonstrated that OPN contributes to metastasis and poor prognosis of cancers, including HCC . Thus, understanding how OPN are involved in maintaining the aggressive phenotype of HCC cells may help to identify novel potential targets for HCC .…”

Section: Discussionmentioning

confidence: 99%

“…Human HCC tissue specimens were obtained following the guidelines approved by the Ethics Committee of the Liver Cancer Institute, Fudan University, and written informed consent was obtained from patients in all cases. Immunohistochemical (IHC) staining was performed as described previously . Briefly, tissue specimens were incubated using antibodies against OPN (1:200 dilution, Abcam, Cambridge, MA, USA), CCR1 (1:100 dilution, Novus, St. Louis, MO, USA) and a biotin‐conjugated secondary antibody and then incubated with an avidin‐biotin‐peroxidase complex.…”

Section: Methodsmentioning

confidence: 99%

“…Osteopontin (OPN) is a secretary phosphorylated glycoprotein that is highly expressed in various human cancers . In our previous studies, we have demonstrated that OPN is one of the leading genes that promote HCC metastasis, and elevated OPN levels in both HCC tissues and plasma are closely related to poor prognosis and postoperative tumor recurrence of HCC patients . Thus, understanding how OPN is involved in maintaining the metastatic phenotype of HCC cells may help to identify novel ways to combat HCC metastasis.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

C‐C chemokine receptor type 1 mediates osteopontin‐promoted metastasis in hepatocellular carcinoma

et al. 2018

Self Cite

View full text Add to dashboard Cite

In the hepatocellular carcinoma (HCC) microenvironment, chemokine receptors play a critical role in tumorigenesis and metastasis. Our previous studies have found that osteopontin (OPN) is a promoter for HCC metastasis. However, the role of chemokine receptors in OPN‐induced HCC metastasis remains unclear. In this study, we demonstrate that OPN is dramatically elevated in HCC tissues with metastasis and that high expression of OPN correlates with poorer overall survival and higher recurrence rate. OPN upregulates chemokine receptor expression, migration, invasion and pulmonary metastasis in HCC. We find that C‐C chemokine receptor type 1 (CCR1) and C‐X‐C chemokine receptor type 6 (CXCR6) are the most upregulated chemokine receptors induced by OPN. CCR1 knockdown results in reduction of migration, invasion and pulmonary metastasis induced by OPN in vitro and in vivo, whereas CXCR6 knockdown does not reverse OPN‐promoted migration and invasion. Moreover, OPN upregulates the expression of CCR1 through activating phosphoinositide 3‐kinase (PI3K)/AKT and hypoxia‐inducible factor 1α (HIF‐1α) in HCC cells. Furthermore, blockade of OPN‐CCR1 axis with CCR1 antagonist significantly restrains the promoting effects of OPN on HCC progression and metastasis. In human HCC tissues, OPN expression shows significantly positive correlation with CCR1 expression, and the patients with high levels of both OPN and CCR1 have the most dismal prognosis. Collectively, our results indicate that the OPN‐CCR1 axis in HCC is important for accelerating tumor metastasis and that CCR1 is a potential therapeutic target for controlling metastasis in HCC patients with high OPN.

show abstract

“…4C, [24]) is totally abolished after vibration. Moreover, VIM which is often stabilized by OPN [25] is significantly reduced. This fact could contribute to enhanced stability of ICAM-1 [26].…”

Section: Quantitative Real-time Pcr (Qpcr) Of Selected Gravitationallmentioning

confidence: 99%

Pathway Analysis Hints Towards Beneficial Effects of Long-Term Vibration on Human Chondrocytes

Lützenberg

Solano

Buken

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Spaceflight negatively influences the function of cartilage tissue in vivo. In vitro human chondrocytes exhibit an altered gene expression of inflammation markers after a two-hour exposure to vibration. Little is known about the impact of long-term vibration on chondrocytes. Methods: Human cartilage cells were exposed for up to 24 h (VIB) on a specialised vibration platform (Vibraplex) simulating the vibration profile which occurs during parabolic flights and compared to static control conditions (CON). Afterwards, they were investigated by phase-contrast microscopy, rhodamine phalloidin staining, microarray analysis, qPCR and western blot analysis. Results: Morphological investigations revealed no changes between CON and VIB chondrocytes. F-Actin staining showed no alterations of the cytoskeleton in VIB compared with CON cells. DAPI and TUNEL staining did not identify apoptotic cells. ICAM-1 was elevated and vimentin, beta-tubulin and osteopontin proteins were significantly reduced in VIB compared to CON cells. qPCR of cytoskeletal genes, ITGB1, SOX3, SOX5, SOX9 did not reveal differential regulations. Microarray analysis detected 13 differentially expressed genes, mostly indicating unspecific stimulations. Pathway analyses demonstrated interactions of PSMD4 and CNOT7 with ICAM. Conclusions: Long-term vibration did not damage human chondrocytes in vitro. The reduction of osteopontin protein and the down-regulation of PSMD4 and TBX15 gene expression suggest that in vitro long-term vibration might even positively influence cultured chondrocytes.

show abstract

Osteopontin promotes epithelial-mesenchymal transition of hepatocellular carcinoma through regulating vimentin

Cited by 62 publications

References 36 publications

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

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

C‐C chemokine receptor type 1 mediates osteopontin‐promoted metastasis in hepatocellular carcinoma

Pathway Analysis Hints Towards Beneficial Effects of Long-Term Vibration on Human Chondrocytes

Contact Info

Product

Resources

About