Overexpression of osteopontin promotes resistance to cisplatin treatment in HCC

Ding, Kun; Fan, Li; Chen, Shijun; Wang, Yanna; Yu, Haifeng; Sun, Yanni; Yu, Jiguang; Wang, Li; Liu, Xiangzhong; Liu, Youde

doi:10.3892/or.2015.4306

Cited by 22 publications

(17 citation statements)

References 41 publications

(47 reference statements)

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“…5,6 Elevated OPN levels participated in many cancers, including breast, prostate, liver, cervical, lung and osteosarcoma. [7][8][9][10][11][12][13] However, the relationship between OPN and cancer stem cells of osteosarcoma is still obscure.…”

Section: Introductionmentioning

confidence: 99%

<p>Cinobufagin Suppresses The Characteristics Of Osteosarcoma Cancer Cells By Inhibiting The IL-6-OPN-STAT3 Pathway</p>

Zhang¹,

Ma²,

Li³

2019

DDDT

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Point your SmartPhone at the code above. If you have a QR code reader the video abstract will appear. Or use: https://youtu.be/a2KF0PMRBDo Background: Current clinical treatments for osteosarcoma are limited by disease recurrence and primary or secondary chemoresistance. Cancer stem-like cells have been proposed to facilitate the initiation, progression, recurrence and chemoresistance of osteosarcoma. Furthermore, previous studies have reported that IL-6-STAT3 pathway is overexpressed in various types of cancer and contributes to cell proliferation, apoptosis, invasion/migration, chemoresistance and modulation of stemness features. Aim: To examined the effect of cinobufagin on cancer progression and modulation of stemness features in osteosarcoma, and investigated the molecular mechanisms underlying such effects. Methods: Human osteosarcoma cell lines U2OS/MG-63 were recruited in this study. Cell proliferation, migration, and invasion were determined by MTT assay, colony formation assay,wound healing assay, and cell invasion assay respectively. Its effect on stemness was assessed by flow cytometry and mammosphere formation. The protein expression levels of related proteins were detected by Western blot. The xenograft model, immunofluorescence staining and immunohistochemistry were used to determine the effect of cinobufagin on tumorigenicity in vivo experiment. Results: We found that cinobufagin suppressed the viability of U2OS/MG-63 spheroids/ parent cells in a time-and dose-dependent manner. Notably, cinobufagin had no effect on the viability of hFOB 1.19 cells. Moreover, cinobufagin induced apoptosis, increased the width of wounds, reduced invasive osteosarcoma spheroids/parent cell numbers and reduced EMT phenotype and OPN levels in U2OS/MG-63 spheroids as well as U2OS/MG-63 parent cells lines. Noticeablely, we found that OPN levels were higher in spheroids group than that in parent cells. In addition, cinobufagin ameliorated the proportion of CD133-positive cells, the size of spheroids and Nanog, Sox-2 and Oct3/4 protein levels. Our in vivo experiments showed that cinobufagin consistently reduced tumor volume,the expressions of OPN, Sox-2, Oct3/4, Nanog and p-STAT3 by the immuno histochemistry staining as well as CD133 expression in tumor tissues by immunofluorescence analysis. From a mechanistic point of view, cinobufagin was shown to inhibit IL-6-OPN-STAT3 signaling pathway. Exogenous IL-6/OE-OPN/overexpression STAT3 attenuated the induction of cinobufagin-mediated apoptosis and the suppression of stemness properties respectively. Conclusion: Collectively, our data demonstrated that cinobufagin inhibited the viability and tumorigenesis capability of osteosarcoma cells by blocking IL-6-OPN-STAT3 signaling pathway. Cinobufagin may therefore represent a promising therapeutic agent for osteosarcoma management.

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Section: Introductionmentioning

confidence: 99%

<p>Cinobufagin Suppresses The Characteristics Of Osteosarcoma Cancer Cells By Inhibiting The IL-6-OPN-STAT3 Pathway</p>

Zhang¹,

Ma²,

Li³

2019

DDDT

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“…These findings suggested the involvement of SPP1_v3 in B‐ALL cell survival and related signalling pathways. In accordance, Ding et al () also demonstrated the involvement of SPP1 in resistance to cisplatin in hepatocellular carcinoma cells by activating the PI3K/AKT signalling pathway, while the blockade of SPP1 pathway promoted chemosensitivity in these cells. Additionally, we found that when SPP1_v3 was knocked down in B‐ALL cells, there was also a significant downregulation of CD44 s and CD44 v9 (SPP1 receptors) transcript expression levels (Fig A).…”

supporting

confidence: 65%

Reinforcing osteopontin as a marker of central nervous system relapse in paediatric B‐cell acute lymphoblastic leukaemia: SPP1 splice variant 3 in the spotlight

et al. 2019

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“…Osteopontin is a multi-functional cytokine that is involved in cell survival, migration and chemotherapy-resistance, including sorafenib-resistance in patients with metastatic renal cell carcinoma [36, 37]. We also observed that sorafenib upregulated osteopontin expression in human hepatoma cell lines and that c-Jun played a role to some extent in this step (Fig 7).…”

Section: Discussionmentioning

confidence: 60%

Overexpression of c-Jun contributes to sorafenib resistance in human hepatoma cell lines

et al. 2017

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BackgroundDespite recent advances in treatment strategies, it is still difficult to cure patients with hepatocellular carcinoma (HCC). Sorafenib is the only approved multiple kinase inhibitor for systemic chemotherapy in patients with advanced HCC. The majority of advanced HCC patients are resistant to sorafenib. The mechanisms of sorafenib resistance are still unknown.MethodsThe expression of molecules involved in the mitogen-activated protein kinase (MAPK) signaling pathway in human hepatoma cell lines was examined in the presence or absence of sorafenib. Apoptosis of human hepatoma cells treated with sorafenib was investigated, and the expression of Jun proto-oncogene (c-Jun) was measured.ResultsThe expression and phosphorylation of c-Jun were enhanced in human hepatoma cell lines after treatment with sorafenib. Inhibiting c-Jun enhanced sorafenib-induced apoptosis. The overexpression of c-Jun impaired sorafenib-induced apoptosis. The expression of osteopontin, one of the established AP-1 target genes, was enhanced after treatment with sorafenib in human hepatoma cell lines.ConclusionsThe protein c-Jun plays a role in sorafenib resistance in human hepatoma cell lines. The modulation and phosphorylation of c-Jun could be a new therapeutic option for enhancing responsiveness to sorafenib. Modulating c-Jun may be useful for certain HCC patients with sorafenib resistance.

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Overexpression of osteopontin promotes resistance to cisplatin treatment in HCC

Cited by 22 publications

References 41 publications

<p>Cinobufagin Suppresses The Characteristics Of Osteosarcoma Cancer Cells By Inhibiting The IL-6-OPN-STAT3 Pathway</p>

<p>Cinobufagin Suppresses The Characteristics Of Osteosarcoma Cancer Cells By Inhibiting The IL-6-OPN-STAT3 Pathway</p>

Reinforcing osteopontin as a marker of central nervous system relapse in paediatric B‐cell acute lymphoblastic leukaemia: SPP1 splice variant 3 in the spotlight

Overexpression of c-Jun contributes to sorafenib resistance in human hepatoma cell lines

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