Intermedin facilitates hepatocellular carcinoma cell survival and invasion via ERK1/2-EGR1/DDIT3 signaling cascade.
Intermedin facilitates hepatocellular carcinoma cell survival and invasion via ERK1/2-EGR1/DDIT3 signaling cascade.
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Intermedin 通过 ERK1/2-EGR1/DDIT3 信号级联促进肝细胞癌细胞存活和侵袭
DOI：
10.1038/s41598-020-80066-x
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发表时间：
2021-01-12
影响因子：
4.6
通讯作者：
Zhang W
中科院分区：
文献类型：
--
作者：
Xiao F;Li H;Feng Z;Huang L;Kong L;Li M;Wang D;Liu F;Zhu Z;Wei Y;Zhang W
肝细胞癌是恶性肿瘤中最常见的一种，具有高度侵袭性，易向远处器官转移。中介素(Intermedin，IMD)是降钙素家族的一种内源性多肽，在包括肝细胞癌在内的癌细胞存活和侵袭过程中发挥重要作用。然而，IMD如何影响肝癌细胞的行为和潜在的机制还没有完全阐明。在这里，我们表明，IMD通过激活ERK1/2-Egr1(早期生长反应1)信号级联来维持重要的动态平衡状态，通过该信号级联，肝癌细胞通过显著增强丝足形成而获得高度侵袭能力。抑制IMD抑制ERK1/2的磷酸化，导致Egr1下调和内质网应激，内质网应激标志物DDIT3(DNA损伤诱导转录本3)上调就是明证。高水平的DDIT3诱导肝癌细胞进入内质网应激相关的凋亡途径。随着我们先前的发现，IMD在改善肿瘤血流灌注的血管重塑过程中发挥关键作用，IMD可能促进肝癌细胞获得更强的侵袭能力和生存益处，并且更容易通过IMD的血管重塑活动获得血供。根据这些结果，阻断IMD活性可能在治疗肝癌方面具有治疗潜力。
As one of the most malignant cancer types, hepatocellular carcinoma (HCC) is highly invasive and capable of metastasizing to distant organs. Intermedin (IMD), an endogenous peptide belonging to the calcitonin family, has been suggested playing important roles in cancer cell survival and invasion, including in HCC. However, how IMD affects the behavior of HCC cells and the underlying mechanisms have not been fully elucidated. Here, we show that IMD maintains an important homeostatic state by activating the ERK1/2-EGR1 (early growth response 1) signaling cascade, through which HCC cells acquire a highly invasive ability via significantly enhanced filopodia formation. The inhibition of IMD blocks the phosphorylation of ERK1/2, resulting in EGR1 downregulation and endoplasmic reticulum stress (ER) stress, which is evidenced by the upregulation of ER stress marker DDIT3 (DNA damage-inducible transcript 3). The high level of DDIT3 induces HCC cells into an ER-stress related apoptotic pathway. Along with our previous finding that IMD plays critical roles in the vascular remodeling process that improves tumor blood perfusion, IMD may facilitate the acquisition of increased invasive abilities and a survival benefit by HCC cells, and it is easier for HCC cells to obtain blood supply via the vascular remodeling activities of IMD. According to these results, blockade of IMD activity may have therapeutic potential in the treatment of HCC.
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