Translation of circHGF RNA encodes an HGF protein variant promoting glioblastoma growth through stimulation of c-MET.
Translation of circHGF RNA encodes an HGF protein variant promoting glioblastoma growth through stimulation of c-MET.
复制标题
DOI：
10.1007/s11060-023-04331-5
复制
发表时间：
2023-05
影响因子：
3.9
通讯作者：
Gera, Joseph
中科院分区：
文献类型：
--
作者：
Saunders, Jacquelyn T. T.;Kumar, Sunil;Benavides-Serrato, Angelica;Holmes, Brent;Benavides, Kennedy E. E.;Bashir, Muhammad T. T.;Nishimura, Robert N. N.;Gera, Joseph
HGF/c-MET信号传导是胶质母细胞瘤（GBM）生长和疾病进展的重要驱动因素。不幸的是，已经发现c-MET靶向疗法在很大程度上是无效的，这表明c-MET活化的额外冗余机制。利用环状RNA的RNA测序（RNA-seq）和核糖体分析，鉴定了circ-HGF（hsa_circ_0080914）在原代GBM中显著上调，并发现其可能编码长度为119个氨基酸的HGF蛋白变体（C-HGF）。对该候选HGF变体进行了表征，并评价了其介导c-MET活化和调节PDX GBM细胞体外生长、运动性和侵袭潜力以及小鼠颅内异种移植物中肿瘤负荷的能力。在circ-HGF RNA内鉴定了内部核糖体进入位点（IRES），其介导编码C-HGF的交叉连接ORF的翻译，并且观察到相对于正常脑组织在GBM中高度表达。还发现C-HGF从GBM细胞分泌，并且浓缩的细胞培养物上清液或重组C-HGF激活c-MET下游的已知信号传导级联。C-HGF显示与c-MET受体直接相互作用，导致其在PDX GBM系中的自磷酸化和活化。C-HGF的敲低导致c-MET信号传导的抑制，并显著抑制细胞生长、运动性和侵袭性，而C-HGF的过表达显示出相反的效果。此外，C-HGF表达的调节调节颅内异种移植PDX GBM模型中的肿瘤生长。这些结果揭示了通过环状RNA编码的HGF蛋白变体激活c-MET的替代机制，其与GBM生物学相关。靶向C-HGF可能为GBM的临床治疗提供一种有前途的方法。在线版本包含补充材料，可通过10.1007/s11060-023-04331-5获得。
HGF/c-MET signaling is a significant driver of glioblastoma (GBM) growth and disease progression. Unfortunately, c-MET targeted therapies have been found to be largely ineffective suggesting additional redundant mechanisms of c-MET activation. Utilizing RNA-sequencing (RNA-seq) and ribosome profiling analyses of circular RNAs, circ-HGF (hsa_circ_0080914) was identified as markedly upregulated in primary GBM and found to potentially encode an HGF protein variant (C-HGF) 119 amino acids in length. This candidate HGF variant was characterized and evaluated for its ability to mediate c-MET activation and regulate PDX GBM cell growth, motility and invasive potential in vitro and tumor burden in intracranial xenografts in mice. An internal ribosome entry site (IRES) was identified within the circ-HGF RNA which mediated translation of the cross-junctional ORF encoding C-HGF and was observed to be highly expressed in GBM relative to normal brain tissue. C-HGF was also found to be secreted from GBM cells and concentrated cell culture supernatants or recombinant C-HGF activated known signaling cascades downstream of c-MET. C-HGF was shown to interact directly with the c-MET receptor resulting in its autophosphorylation and activation in PDX GBM lines. Knockdown of C-HGF resulted in suppression of c-MET signaling and marked inhibition of cell growth, motility and invasiveness, whereas overexpression of C-HGF displayed the opposite effects. Additionally, modulation of C-HGF expression regulated tumor growth in intracranial xenografted PDX GBM models. These results reveal an alternative mechanism of c-MET activation via a circular RNA encoded HGF protein variant which is relevant in GBM biology. Targeting C-HGF may offer a promising approach for GBM clinical management. The online version contains supplementary material available at 10.1007/s11060-023-04331-5.
登录
查看更多内容
影响因子：
5.6
作者：
Prats AC;David F;Diallo LH;Roussel E;Tatin F;Garmy-Susini B;Lacazette E
通讯作者：
Lacazette E
影响因子：
3.5
作者：
Sehta P;Wilhelm AM;Lin SJ;Urman MA;MacNeil HA;Fuchs G
通讯作者：
Fuchs G
N6-甲基腺苷修饰与环状 RNA 之间的串扰：当前理解和未来方向
影响因子：
37.3
作者：
Wang X;Ma R;Zhang X;Cui L;Ding Y;Shi W;Guo C;Shi Y
通讯作者：
Shi Y
影响因子：
8
作者：
Hammond, DE;Urbé, S;Clague, MJ
通讯作者：
Clague, MJ
影响因子：
4.5
作者：
Salzman J;Chen RE;Olsen MN;Wang PL;Brown PO
通讯作者：
Brown PO