Osteopontin Overexpression Induced Tumor Progression and Chemoresistance to Oxaliplatin through Induction of Stem-Like Properties in Human Colorectal Cancer

Ng, Lui; Wan, Timothy Ming‐Hun; Chow, Albert H.L.; Iyer, Deepak Narayanan; Man, Johnny Hon-Wai; Chen, Guanghua; Yau, Thomas; Lo, Oswens Siu-Hung; Foo, Chi Chung; Poon, Jensen T. C.; Poon, Ronnie Tung Ping; Pang, Roberta; Law, Wai Lun

doi:10.1155/2015/247892

Cited by 45 publications

(41 citation statements)

References 21 publications

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“…OPN has been shown to exert a positive effect on the modulation of stemness traits in hepatocellular carcinoma, lung cancer, colorectal cancer, and pancreatic cancer. [47][48][49][50] Figure 6 shows that OE-OPN neutralized the cinobufagininduced reduction in spheroid size and p-STAT3(Tyr727) along with p-STAT3(Ser705), Bax, Bcl-2, caspase-3, cleaved PARP, Nanog, Sox-2 and Oct3/4 levels. We also found that si-OPN plus cinobufagin treatment synergistically downregulated the expression of these indicators which suggested that OPN participates in the cinobufagininduced suppression of stemness features in osteosarcoma spheriods.…”

Section: Discussionmentioning

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: Discussionmentioning

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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“…OPN is commonly found in some mineralized tissues as an extracellular matrix (ECM), and it also behaves as a secreted protein in body fluids, such as milk, blood, urine, saliva, seminal fluid and bile 58 . As a result of its diverse distribution, OPN is involved in multiple steps of tumor biology, including cell proliferation, survival, angiogenesis, chemoresistance, stem-like properties, tumor invasion, and metastasis 59 . Specifically, as referred to the publications through 2000 to 2015 with the keywords 'osteopontin AND cancer' on PubMed database, it is observed that elevated OPN expression in serum samples has been used as a prime mediator of various human cancers.…”

Section: The Involvement Of Opn In Tumor Biologymentioning

confidence: 99%

“…In their further work, the transcription level of OPN in 84 CRC patients was well characterized, and the overexpression of OPN in DLD1-OPN cells induced cell survival and chemoresistance to oxaliplatin treatment. Moreover, OPN overexpression was involved in tumor metastasis and the decrease of the survival rate of CRC patients, by inducing the stem-like property of CRC cells via overexpressing SOX2 59 , 68 .…”

Section: The Involvement Of Opn In Tumor Biologymentioning

confidence: 99%

Osteopontin -- a promising biomarker for cancer therapy

2017

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Osteopontin (OPN), a multifunctional protein, has emerged as a potentially valuable biomarker for diagnosing and treating cancers. Recent research focuses on its involvement in tumor biology including the cell proliferation, survival, angiogenesis, invasion, and metastasis. Understanding the molecular mechanisms and pharmacological effects of OPN in cancer development could lead to new targets for improving cancer diagnosis and treatment.This review explains how the structurally conserved domains of OPN are associated with OPN signaling mediators and CD44, and how the conserved OPN domains determine biological functions. The authors have reviewed representative works of OPN expression in breast cancer and colorectal cancer to elucidate the relationship between OPN and cancer/tumor biology. It has also been shown that the prognostic sensitivity in non-small cell lung cancer, hepatocellular carcinoma, gastric cancer, and ovarian cancer improved compared to the individual marker when OPN was analyzed in conjunction with other markers. The therapeutic approaches based on OPN inhibitors are discussed to illustrate recent research progress. Previous clinical data has indicated that OPN has played a unique role in cancer development, but further investigation is required to understand the underlying mechanism. More clinical trials are also required to examine the applicability and efficacy of OPN inhibitors in cancer therapy.

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“…Another interesting fact is that several studies have shown the deposition in human coronary arteries of osteopontin, a member of a category of the NCPs termed SIBLING (Small Integrin‐Binding Ligand, N‐linked Glycoprotein), which have been associated with atheroma calcification and tumors progression , besides other complications. Once the dentin and cementum present osteopontin and other SIBLING proteins in their composition, with similar role in mineralization and cellular adhesion; theoretically, some of these proteins released from dentin as result of orthodontic root resorption may also circulate through the body.…”

Section: Discussionmentioning

confidence: 99%

Circulating dentinal antigen‐antibody immune complexes during orthodontic tooth movement in rats

Costa

Hidalgo

Consolaro

et al. 2016

J Oral Pathology Medicine

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Osteopontin Overexpression Induced Tumor Progression and Chemoresistance to Oxaliplatin through Induction of Stem-Like Properties in Human Colorectal Cancer

Cited by 45 publications

References 21 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>

Osteopontin -- a promising biomarker for cancer therapy

Circulating dentinal antigen‐antibody immune complexes during orthodontic tooth movement in rats

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