Zhou Lei, Ding Lihua, Liu Jie, Zhang Yanan, Luo Xiaoli, Zhao Lichun, Ren Jun
Department of Medical Oncology, Capital Medical University Cancer Center, Beijing Shijitan Hospital, Beijing 100038, P.R. China.
Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing 100850, P.R. China.
J Cancer Res Ther. 2018 Sep;14(Supplement):S767-S773. doi: 10.4103/0973-1482.187304.
Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide.
To investigate the mechanisms of paclitaxel resistance in hepatocellular carcinoma cells and find promising molecular target for HCC therapy.
To investigate the effects of FHL1 on chemo resistance in HCC cells, we generated FHL1 knock-down stable cell lines with HepG2 and SMMC7721 cells. Cell viability assay, colony formation and xenograft experiments assay were performed to detect effect of FHL1 on Paclitaxel or Oxaliplatin resistance in vitro and in vivo. Caspase activity assay was performed to explore the activation of caspase-3 and caspase-9 in paclitaxel treated FHL1-knockdown HepG2 cells.
In the present study we have investigated that four-and-a-half LIM protein 1 (FHL1), which plays an important role in the development of cancer, is associated with both the chemo resistance of hepatocellular carcinomas cells in vitro and in vivo. Knockdown of FHL1 significantly enhanced the sensitivity of paclitaxel, but had no effects on sensitivity of oxaliplatin. Moreover, knockdown of FHL1 promoted the activation of caspase-3 and caspase-9, which were induced by paclitaxel. Interestingly, FHL1 negatively regulates the chemo resistance of HCC in xenografted nude mice.
FHL1 promote paclitaxel resistance in hepatocellular carcinomas cells through regulating apoptosis induced by paclitaxel, suggesting that FHL1 may be a promising molecular target for HCC therapy.
肝细胞癌（HCC）是全球癌症死亡的第三大主要原因。
研究肝癌细胞中紫杉醇耐药的机制，并寻找有前景的肝癌治疗分子靶点。
为研究FHL1对肝癌细胞化疗耐药的影响，我们构建了HepG2和SMMC7721细胞的FHL1基因敲低稳定细胞系。进行细胞活力测定、集落形成和异种移植实验，以检测FHL1对紫杉醇或奥沙利铂在体外和体内耐药性的影响。进行半胱天冬酶活性测定，以探究紫杉醇处理的FHL1基因敲低的HepG2细胞中半胱天冬酶-3和半胱天冬酶-9的激活情况。
在本研究中，我们发现四半LIM蛋白1（FHL1）在癌症发展中起重要作用，它与肝癌细胞在体外和体内的化疗耐药性均相关。敲低FHL1显著增强了对紫杉醇的敏感性，但对奥沙利铂的敏感性没有影响。此外，敲低FHL1促进了紫杉醇诱导的半胱天冬酶-3和半胱天冬酶-9的激活。有趣的是，FHL1在异种移植裸鼠中负向调节肝癌的化疗耐药性。
FHL1通过调节紫杉醇诱导的细胞凋亡促进肝癌细胞对紫杉醇的耐药性，提示FHL1可能是肝癌治疗中有前景的分子靶点。
