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Autocrine parathyroid hormone-like hormone promotes intrahepatic cholangiocarcinoma cell proliferation via increased ERK/JNK-ATF2-cyclinD1 signaling.
- Source :
-
Journal of translational medicine [J Transl Med] 2017 Nov 25; Vol. 15 (1), pp. 238. Date of Electronic Publication: 2017 Nov 25. - Publication Year :
- 2017
-
Abstract
- Background and Aims: Intrahepatic cholangiocarcinoma (ICC) is an aggressive tumor with a high fatality rate. It was recently found that parathyroid hormone-like hormone (PTHLH) was frequently overexpressed in ICC compared with non-tumor tissue. This study aimed to elucidate the underlying mechanisms of PTHLH in ICC development.<br />Methods: The CCK-8 assay, colony formation assays, flow cytometry and a xenograft model were used to examine the role of PTHLH in ICC cells proliferation. Immunohistochemistry (IHC) and western blot assays were used to detect target proteins. Luciferase reporter, chromatin immunoprecipitation (ChIP) and DNA pull-down assays were used to verify the transcription regulation of activating transcription factor-2 (ATF2).<br />Results: PTHLH was significantly upregulated in ICC compared with adjacent and normal tissues. Upregulation of PTHLH indicated a poor pathological differentiation and intrahepatic metastasis. Functional study demonstrated that PTHLH silencing markedly suppressed ICC cells growth, while specific overexpression of PTHLH has the opposite effect. Mechanistically, secreted PTHLH could promote ICC cell growth by activating extracellular signal-related kinase (ERK) and c-Jun N-terminal kinase (JNK) signaling pathways, and subsequently upregulated ATF2 and cyclinD1 expression. Further study found that the promoter activity of PTHLH were negatively regulated by ATF2, indicating that a negative feedback loop exists.<br />Conclusions: Our findings demonstrated that the ICC-secreted PTHLH plays a characteristic growth-promoting role through activating the canonical ERK/JNK-ATF2-cyclinD1 signaling pathways in ICC development. We identified a negative feedback loop formed by ATF2 and PTHLH. In this study, we explored the therapeutic implication for ICC patients.
- Subjects :
- Activating Transcription Factor 2 metabolism
Adult
Aged
Aged, 80 and over
Animals
Autocrine Communication physiology
Bile Duct Neoplasms genetics
Bile Ducts, Intrahepatic metabolism
Bile Ducts, Intrahepatic pathology
Cell Line, Tumor
Cholangiocarcinoma genetics
Cyclin D1 metabolism
Extracellular Signal-Regulated MAP Kinases metabolism
Female
Gene Expression Regulation, Neoplastic drug effects
Humans
JNK Mitogen-Activated Protein Kinases metabolism
Male
Mice
Mice, Inbred BALB C
Mice, Nude
Middle Aged
Paraneoplastic Endocrine Syndromes genetics
Paraneoplastic Endocrine Syndromes metabolism
Paraneoplastic Endocrine Syndromes pathology
Parathyroid Hormone-Related Protein pharmacology
Parathyroid Hormone-Related Protein physiology
Signal Transduction drug effects
Bile Duct Neoplasms metabolism
Bile Duct Neoplasms pathology
Cell Proliferation drug effects
Cell Proliferation genetics
Cholangiocarcinoma metabolism
Cholangiocarcinoma pathology
Parathyroid Hormone-Related Protein metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1479-5876
- Volume :
- 15
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of translational medicine
- Publication Type :
- Academic Journal
- Accession number :
- 29178939
- Full Text :
- https://doi.org/10.1186/s12967-017-1342-1