CCN2 promotes drug resistance in osteosarcoma by enhancing ABCG2 expression

Tsai, Hsiao‐Chi; Chang, An‐Chen; Tsai, Cheng-Han; Huang, Yuan‐Li; Gan, Lijun; Chen, Chi‐Kuan; Liu, Shih‐Chia; Huang, Te‐Yang; Fong, Yi‐Chin; Tang, Chih‐Hsin

doi:10.1002/jcp.27611

Cited by 18 publications

(17 citation statements)

References 56 publications

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“…29 Moreover, xenograft experiments conducted by Tsai et al suggested that CCN2 upregulation protected OS cells from doxorubicin, and the therapeutic efficacy was remarkably promoted when CCN2 was reduced. 30 However, the relevance of CCN2 in chemoresistance of OS cells to DDP and taxanes was not clarified yet, which might be the direction for our further experiments.…”

Section: Discussionmentioning

confidence: 96%

<p>MicroRNA-584 Impairs Cellular Proliferation and Sensitizes Osteosarcoma Cells to Cisplatin and Taxanes by Targeting CCN2</p>

Li¹,

Kong²,

Zang³

et al. 2020

CMAR

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Background: Osteosarcoma (OS), an aggressive malignant neoplasm, exhibits osteoblastic differentiation. Cisplatin (DDP) and taxanes are among the most effective drugs for OS patients. Nevertheless, the drug resistance remains a main limitation to efficacious chemotherapy in OS. The current report sets to explore the biological function of microRNA-584 (miR-584) and the potential mechanism underlying OS cells resistance to these two drugs. Materials and Methods: The expression profiles of miR-584 and connective tissue growth factor (CTGF, CCN2) in OS tissue samples and cell lines were tested by means of reverse transcription-quantitative polymerase chain reaction and Western blot. U2OS and MG63 cell lines were delivered with miR-584 mimic alone or plus CCN2 to excavate theirs functions by cell counting kit-8 and EdU, flow cytometric analysis, as well as transwell assay, severally. Western bot analysis was conducted to examine the expression of IκBα, pIκBα, NF-κB and pNF-κB. Dual-luciferase reporter gene assay was carried out to assess the targets of miR-584. Results: The downregulation of miR-584 was identified in OS tissues and cells, which was closely linked to the dismal prognosis of OS patients. Overexpression of miR-584 repressed cell viability, migration as well as invasion, potentiated apoptosis and sensitized OS cells to DDP and taxanes. Mechanism investigation specified a direct targeting relationship between CCN2 and miR-584 in OS. Conclusion: In conclusion, miR-584 has the potency to act as a therapeutic maneuver for OS mainly by inducing the chemosensitivity of OS cells to DDP and taxanes.

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Section: Discussionmentioning

confidence: 96%

<p>MicroRNA-584 Impairs Cellular Proliferation and Sensitizes Osteosarcoma Cells to Cisplatin and Taxanes by Targeting CCN2</p>

Li¹,

Kong²,

Zang³

et al. 2020

CMAR

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“…High ABCG2 expression has been identified in a variety of solid tumors and has been correlated with poorer clinical outcomes [8][9][10]. In a recent study, Tsai et al [18] reported that ABCG2 overexpression could decrease the therapeutic effect of DOX in OS cells. For the first time, we confirmed the role of ABCG2 in the development of chemoresistance using the established DOX-resistant OS cell lines.…”

Section: Discussionmentioning

confidence: 99%

High expression of ABCG2 is associated with chemotherapy resistance of osteosarcoma

et al. 2021

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Objectives Previous studies showed overexpression of ABCG2 in a variety of tumor tissues, which could potentially indicate the probability of chemotherapy resistance. This study aimed to reveal the role of ABCG2 in the development of chemotherapy resistance and the prognosis of osteosarcoma (OS). Methods Sixty-eight OS patients were included in this study. Tumor tissues were collected for each patient during surgery. DOX-resistant OS cell lines were induced by consecutive exposure of gradually increasing concentration of DOX to the parental cell lines. Lentivirus was used for the knockdown of ABCG2 in OS cells. Cells were treated with the gradient concentration of DOX, and the viability was assessed by CCK8 assay. Total RNA was isolated from the tumor tissues or tumor cells, and the expression of ABCG2 was analyzed by qPCR. The relationship between ABCG2 expression and clinicopathological characteristics of the patients was analyzed using Student’s t test or the Chi-square test. The overall survival time was calculated by the Kaplan-Meier method and analyzed by the log-rank test. p < 0.05 was considered statistically significant. Results DOX-resistant OS cells were successfully established through continuous exposure to DOX. Forty-eight hours after DOX exposure, the IC 50 value of DOX-resistant HOS cells and DOX-resistant U2OS was 3.5 μM and 3.25 μM, respectively. By contrast, those of the untreated HOS and U2OS cells were 1.15 μM and 0.93 μM, respectively (p < 0.01). The mRNA expression level of ABCG2 was significantly increased in DOX-resistant cell lines. The CCK-8 assay showed that the DOX-resistant HOS cells and DOX-resistant U2OS cells transfected with ShABCG2 were more sensitive to the DOX treatment than those transfected with ShCtrl. Analysis of gene expression in OS tissues showed remarkably higher expression of ABCG2 as compared with adjacent normal tissues (p < 0.01). Patients with high expression level of ABCG2 had obviously decreased overall survival time than the patients with normal expression (p < 0.01). Conclusions ABCG2 expression level was significantly associated with the resistance to chemotherapy and the overall survival of OS patients. ABCG2 may be a promising therapeutic target for OS patients.

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“…Inhibition of the Notch pathway resulted in downregulation of MRP1 expression, overcoming chemoresistance in human OS cells (Li et al, 2016). BCRP upregulation was reported to be a reason of CCN2 overexpression‐caused promotion of doxorubicin resistance (Tsai et al, 2019). Therefore, we concluded that poncirin overcame cisplatin resistance in cisplatin‐resistant OS cells by downregulating MDR1, MRP1, and BCRP.…”

Section: Discussionmentioning

confidence: 99%

Poncirin downregulates ATP‐binding cassette transporters to enhance cisplatin sensitivity in cisplatin‐resistant osteosarcoma cells

Zhao

Zhang

2020

Phytotherapy Research

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Poncirin, a flavanone glycoside with bitter taste extracted from dried immature fruit of Poncirus trifoliate, exhibits multiple biological activities including anti‐tumor activity. Our study aimed to determine the effect and potential mechanism of poncirin on cisplatin resistance in osteosarcoma (OS) cells. CCK‐8, flow cytometry analysis, and caspase‐3/7 activity assays were used to evaluate cisplatin sensitivity. The expression changes of multidrug resistance 1 (MDR1), multidrug resistance‐associated protein (MRP1), breast cancer resistance protein (BCRP), and phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) pathway‐related proteins were detected by RT‐qPCR or western blot analyses. Results showed that poncirin exposure enhanced cisplatin sensitivity, promoted apoptosis, and increased caspase‐3/7 activity in cisplatin‐resistant OS cells. Poncirin decreased the expression levels of MDR1, MRP1, and BCRP, and inhibited the PI3K/Akt signaling in OS cells. Rescue experiments suggested that activation of the PI3K/Akt signaling by 740Y‐P abolished poncirin‐induced expression reduction of MDR1, MRP1, and BCRP, and attenuated the facilitative effects of poncirin on cisplatin sensitivity and apoptosis in cisplatin‐resistant OS cells. In summary, poncirin suppressed cisplatin resistance in cisplatin‐resistant OS cells by downregulating the expression of MDR1, MRP1, and BCRP through inhibiting the PI3K/Akt pathway.

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CCN2 promotes drug resistance in osteosarcoma by enhancing ABCG2 expression

Cited by 18 publications

References 56 publications

<p>MicroRNA-584 Impairs Cellular Proliferation and Sensitizes Osteosarcoma Cells to Cisplatin and Taxanes by Targeting CCN2</p>

<p>MicroRNA-584 Impairs Cellular Proliferation and Sensitizes Osteosarcoma Cells to Cisplatin and Taxanes by Targeting CCN2</p>

High expression of ABCG2 is associated with chemotherapy resistance of osteosarcoma

Poncirin downregulates ATP‐binding cassette transporters to enhance cisplatin sensitivity in cisplatin‐resistant osteosarcoma cells

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