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视杆细胞特异性光感受器环磷酸鸟苷磷酸二酯酶（PDE6D）的δ亚基促进肝细胞癌进展。

The Delta Subunit of Rod-Specific Photoreceptor cGMP Phosphodiesterase (PDE6D) Contributes to Hepatocellular Carcinoma Progression.

作者信息

Dietrich Peter, Hellerbrand Claus, Bosserhoff Anja

机构信息

Institute of Biochemistry, Emil-Fischer-Zentrum, Friedrich-Alexander-University, Erlangen-Nürnberg, 91054 Erlangen, Germany.

Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-University, Erlangen-Nürnberg, 91054 Erlangen, Germany.

出版信息

Cancers (Basel). 2019 Mar 21;11(3):398. doi: 10.3390/cancers11030398.

DOI:10.3390/cancers11030398
PMID:30901922
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6468542/
Abstract

Emerging evidence reveals crucial roles of wild type RAS in liver cancer. The delta subunit of (PDE6D) regulates the trafficking of RAS proteins to the plasma membrane and thereby contributes to RAS activation. However, the expression and specific function of PDE6D in hepatocellular carcinoma (HCC) were completely unknown. In this study, PDE6D was newly found to be markedly upregulated in HCC tissues and cell lines. Overexpression of PDE6D in HCC correlated with enhanced tumor stages, tumor grading, and ERK activation. PDE6D depletion significantly reduced proliferation, clonogenicity, and migration of HCC cells. Moreover, PDE6D was induced by TGF-β1, the mediator of stemness, epithelial-mesenchymal transition (EMT), and chemoresistance. In non-resistant cells, overexpression of PDE6D conferred resistance to sorafenib-induced toxicity. Further, PDE6D was overexpressed in sorafenib resistance, and inhibition of PDE6D reduced proliferation and migration in sorafenib-resistant HCC cells. Together, PDE6D was found to be overexpressed in liver cancer and correlated with tumor stages, grading, and ERK activation. Moreover, PDE6D contributed to migration, proliferation, and sorafenib resistance in HCC cells, therefore representing a potential novel therapeutic target.

摘要

新出现的证据揭示了野生型RAS在肝癌中的关键作用。磷酸二酯酶6D（PDE6D）的δ亚基调节RAS蛋白向质膜的转运，从而促进RAS激活。然而，PDE6D在肝细胞癌（HCC）中的表达及具体功能完全未知。在本研究中，新发现PDE6D在HCC组织和细胞系中显著上调。HCC中PDE6D的过表达与肿瘤分期、肿瘤分级及ERK激活增强相关。PDE6D缺失显著降低HCC细胞的增殖、克隆形成能力及迁移能力。此外，PDE6D由干性、上皮-间质转化（EMT）及化疗耐药的介质转化生长因子-β1（TGF-β1）诱导。在非耐药细胞中，PDE6D过表达赋予对索拉非尼诱导毒性的耐药性。此外，PDE6D在索拉非尼耐药中过表达，抑制PDE6D可降低索拉非尼耐药的HCC细胞的增殖和迁移。总之，发现PDE6D在肝癌中过表达，且与肿瘤分期、分级及ERK激活相关。此外，PDE6D促进HCC细胞的迁移、增殖及索拉非尼耐药，因此代表一个潜在的新型治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2854/6468542/8d50a6b96acf/cancers-11-00398-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2854/6468542/4088cbb9ad4e/cancers-11-00398-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2854/6468542/455b6b831a5e/cancers-11-00398-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2854/6468542/2e78172c0edf/cancers-11-00398-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2854/6468542/2308c24aa1b3/cancers-11-00398-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2854/6468542/c51df4044eea/cancers-11-00398-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2854/6468542/8d50a6b96acf/cancers-11-00398-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2854/6468542/4088cbb9ad4e/cancers-11-00398-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2854/6468542/455b6b831a5e/cancers-11-00398-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2854/6468542/2e78172c0edf/cancers-11-00398-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2854/6468542/2308c24aa1b3/cancers-11-00398-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2854/6468542/c51df4044eea/cancers-11-00398-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2854/6468542/8d50a6b96acf/cancers-11-00398-g006.jpg

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