LPAATβ在骨肉瘤顺铂耐药中的作用及机制研究

Previous studies including our previous research demonstrate LPAATβ closely relates to malignant development of tumors. However, there are still no direct evidence to prove LPAATβ can regulate resistance of chemotherapy drugs for tumors. Our previous research demonstrates overexpression of LPAATβ could obviously deccrease sensibility of cisplatin and upregulate expression levels of phosphorylated Erk, Akt and mTOR in osteosarcoma cell line 143B. Inhibition of PI3K/Akt/mTOR and Raf/MEK/Erk signal ways could inverse above effects. Besides, expression of LPAATβ is obviously higher in cisplatin-resistant cell line 143B-CR induced from 143B by method of gradient concentration than in 143B. Thurs, according to previous studies and our previous research, we suggest a research hypothesis that LPAATβ promotes resistance of cisplatin for osteosarcoma by activating PI3K/Akt/mTOR and Raf/MEK/Erk signal ways. For proving this hypothesis and hoping to obtain a new therapy target, our research plans to deeply research effects and mechanisms of LPAATβ to resistance of cisplatin for ostesarcoma through cell, animal and clinical sample levels from above basis.

国内外和我们的前期研究表明LPAATβ与肿瘤的恶性进展密切相关，然而尚无揭示LPAATβ调控肿瘤细胞化疗耐药的直接证据。我们前期研究发现：在骨肉瘤143B细胞株中，过表达LPAATβ能够显著降低骨肉瘤细胞顺铂敏感性并上调磷酸化Erk、Akt及mTOR表达水平。抑制PI3K/Akt/mTOR及Raf/MEK/Erk信号通路可逆转上述效应。此外，用浓度梯度法诱导骨肉瘤143B顺铂耐药细胞株（143B-CR）中LPAATβ表达显著高于143B细胞株。因此，基于我们前期研究发现及以往的认识基础，我们提出"LPAATβ通过激活PI3K/Akt/mTOR和MEK/Erk信号通路促进骨肉瘤细胞顺铂耐药"这一研究假设。为证实该假设，本研究在上述基础上，通过细胞、动物和临床标本水平深入探讨LPAATβ对骨肉瘤细胞顺铂耐药的影响及其机制，以期获得新的干预靶点。

国内外和我们的前期研究表明LPAATβ与肿瘤的恶性进展密切相关，然而尚无揭示LPAATβ调控肿瘤细胞化疗耐药的直接证据。基于我们前期研究发现及以往的认识基础，我们提出"LPAATβ通过激活PI3K/Akt/mTOR和MEK/Erk信号通路促进骨肉瘤细胞顺铂耐药"这一研究假设。为证实该假设，本研究在上述基础上，通过细胞、动物和临床标本水平深入探讨LPAATβ对骨肉瘤细胞顺铂耐药的影响及其机制，以期获得新的干预靶点。我们研究发现：在骨肉瘤细胞株中，沉默表达LPAATβ能够显著降低骨肉瘤细胞顺铂敏感性并下调调磷酸化Erk、Akt及mTOR表达水平。抑制PI3K/Akt/mTOR及Raf/MEK/Erk信号通路可逆转上述效应。此外，用浓度梯度法诱导骨肉瘤顺铂耐药细胞株中LPAATβ表达显著高于亲本细胞株。