TPD52L2 impacts proliferation, invasiveness and apoptosis of glioblastoma cells via modulation of wnt/β-catenin/snail signaling
TPD52L2 impacts proliferation, invasiveness and apoptosis of glioblastoma cells via modulation of wnt/β-catenin/snail signaling
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TPD52L2 通过调节 wnt/β-catenin/snail 信号传导影响胶质母细胞瘤细胞的增殖、侵袭和凋亡
DOI：
10.1093/carcin/bgx125
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发表时间：
2018-02-01
期刊：
影响因子：
4.7
通讯作者：
Lu Yun-tao
中科院分区：
文献类型：
--
作者：
Zhou Qiang;Li Jun-jie;Lu Yun-tao
肿瘤内的异质性极大地阻碍了胶质母细胞瘤靶向治疗的效率。为了解释异质性的潜在机制，分别从T1 Gd增强型肿瘤病变(PNC)和T1 Gd增强型核心病变(ECs)的边缘分离了患者来源的成人GBM细胞。在ECs和U87 MG细胞系中进行单克隆培养，筛选出具有不同生物学表型的克隆。同时从ECs和U87细胞系中分离出不同表型的单细胞克隆。PNC、GCs(H)和U87(H)的细胞突起时间分别长于ECs、GCs(L)和U87(L)。突起时间越长的细胞株侵袭能力越强，对替莫唑胺(TMZ)和辐射的敏感性越低。随后，通过蛋白质组学分析证实TPD52L2是调节细胞异质性的功能蛋白。体内、外TPD52L2表达下调可促进细胞侵袭，抑制细胞增殖率和化疗敏感性，而TPD52L2过表达则相反。CTNNB1/β-catenin和SNAI1/Snail介导的EMT过程通过上调CTNNB1/β-catenin和SNAI1/Snail介导的EMT过程促进侵袭。此外，对我中心88例GBM患者的临床资料进行了分析，以揭示TPD52L2对GBM预后的影响。TPD52L2的低表达加剧了接受标准放疗加伴随和辅助TMZ治疗的GBM患者的预后(Stupp策略)。综上所述，TPD52L2是影响GBM预后的重要标志物。
Intratumoral heterogeneity greatly hinders efficiency of target therapy in glioblastoma (GBM). To decipher the underlying mechanisms of heterogeneity, patient-derived adult GBM cells were separately isolated from margins of T1 gadolinium enhancing tumor lesions (PNCs) and T1 gadolinium enhancing core lesions (ECs). Single clone culture was conducted in ECs and U87MG cell line to screen clones with distinct biological phenotypes. Single cell clones with diverse phenotypes were simultaneously separated from ECs and U87 cell line. PNCs, GCs(H) and U87(H) exhibited longer cellular protrusion than ECs, GCs(L) and U87(L), respectively. Cell strains with longer protrusion exhibited higher invasive ability and lower sensitivity to temozolomide (TMZ) and radiation. Subsequently, TPD52L2 was verified as the functional protein to regulate the cellular heterogeneity by the proteomics analysis. Downregulation of TPD52L2 enhanced cell invasion whereas inhibited cell proliferation rate and sensitivity to chemotherapy in vivo and in vitro, this condition was reversed when TPD52L2 was overexpressed. The invasiveness was facilitated by up-regulating CTNNB1/beta-catenin and SNAI1/Snail mediated EMT process. In addition, the clinical data of 88 GBM cases in our neurosurgery center was analyzed to reveal the influence of TPD52L2 in the prognosis of GBM. Low expression of TPD52L2 exacerbated prognosis of GBM patients received standard radiotherapy plus concomitant and adjuvant TMZ (Stupp strategy). Taken together, TPD52L2 is an important biomarker influencing GBM prognosis.