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SMS1和SMS2对胶质瘤进展的相反作用及其在对2-羟基油酸治疗反应中的价值。

The Opposing Contribution of SMS1 and SMS2 to Glioma Progression and Their Value in the Therapeutic Response to 2OHOA.

作者信息

Fernández-García Paula, Rosselló Catalina A, Rodríguez-Lorca Raquel, Beteta-Göbel Roberto, Fernández-Díaz Javier, Lladó Victoria, Busquets Xavier, Escribá Pablo V

机构信息

Laboratory of Molecular Cell Biomedicine, University of the Balearic Islands, 07122 Palma de Mallorca, Spain.

Lipopharma Therapeutics, Isaac Newton, 07121 Palma de Mallorca, Spain.

出版信息

Cancers (Basel). 2019 Jan 14;11(1):88. doi: 10.3390/cancers11010088.

DOI:10.3390/cancers11010088
PMID:30646599
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6356341/
Abstract

: 2-Hydroxyoleic acid (2OHOA) is particularly active against glioblastoma multiforme (GBM) and successfully finished a phase I/IIA trial in patients with glioma and other advanced solid tumors. However, its mechanism of action is not fully known. : The relationship between SMS1 and SMS2 expressions (mRNA) and overall survival in 329 glioma patients was investigated, and so was the correlation between SMS expression and 2OHOA's efficacy. The opposing role of SMS isoforms in 2OHOA's mechanism of action and in GBM cell growth, differentiation and death, was studied overexpressing or silencing them in human GBM cells. : Patients with high-SMS1 plus low-SMS2 expression had a 5-year survival ~10-fold higher than patients with low-SMS1 plus high-SMS2 expression. SMS1 and SMS2 also had opposing effect on GBM cell survival and 2OHOA's IC correlated with basal SMS1 levels and treatment induced changes in SMS1/SMS2 ratio. SMSs expression disparately affected 2OHOA's cancer cell proliferation, differentiation, ER-stress and autophagy. : SMS1 and SMS2 showed opposite associations with glioma patient survival, glioma cell growth and response to 2OHOA treatment. SMSs signature could constitute a valuable prognostic biomarker, with high SMS1 and low SMS2 being a better disease prognosis. Additionally, low basal SMS1 mRNA levels predict positive response to 2OHOA.

摘要

2-羟基油酸（2OHOA）对多形性胶质母细胞瘤（GBM）具有特别的活性，并成功完成了针对胶质瘤和其他晚期实体瘤患者的I/IIA期试验。然而，其作用机制尚不完全清楚。

研究了329例胶质瘤患者中SMS1和SMS2表达（mRNA）与总生存期的关系，以及SMS表达与2OHOA疗效之间的相关性。通过在人GBM细胞中过表达或沉默SMS亚型，研究了它们在2OHOA作用机制以及GBM细胞生长、分化和死亡中的相反作用。

SMS1高表达加SMS2低表达的患者5年生存率比SMS1低表达加SMS2高表达的患者高约10倍。SMS1和SMS2对GBM细胞存活也有相反作用，2OHOA的IC与基础SMS1水平以及治疗诱导的SMS1/SMS2比值变化相关。SMS的表达对2OHOA的癌细胞增殖、分化、内质网应激和自噬有不同影响。

SMS1和SMS2与胶质瘤患者生存率以及胶质瘤细胞生长和对2OHOA治疗的反应呈相反关系。SMS特征可能构成一种有价值的预后生物标志物，SMS1高表达和SMS2低表达预示着更好的疾病预后。此外，基础SMS1 mRNA水平低预示着对2OHOA有阳性反应。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4e2/6356341/1b1de58886bc/cancers-11-00088-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4e2/6356341/5fb9c3027649/cancers-11-00088-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4e2/6356341/a84fee52f185/cancers-11-00088-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4e2/6356341/b3b5e7fddd3e/cancers-11-00088-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4e2/6356341/1d08f1f80388/cancers-11-00088-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4e2/6356341/f1c98c1e3978/cancers-11-00088-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4e2/6356341/1b1de58886bc/cancers-11-00088-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4e2/6356341/5fb9c3027649/cancers-11-00088-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4e2/6356341/a84fee52f185/cancers-11-00088-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4e2/6356341/b3b5e7fddd3e/cancers-11-00088-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4e2/6356341/1d08f1f80388/cancers-11-00088-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4e2/6356341/f1c98c1e3978/cancers-11-00088-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4e2/6356341/1b1de58886bc/cancers-11-00088-g006.jpg

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