LHPP suppresses tumorigenesis of intrahepatic cholangiocarcinoma by inhibiting the TGFβ/smad signaling pathway

Dan Wang; Zhouyu Ning; Zhenfeng Zhu; Chenyue Zhang; Peng Wang; Zhiqiang Meng

doi:10.1016/j.biocel.2020.105845

LHPP suppresses tumorigenesis of intrahepatic cholangiocarcinoma by inhibiting the TGFβ/smad signaling pathway

Int J Biochem Cell Biol. 2021 Mar:132:105845. doi: 10.1016/j.biocel.2020.105845. Epub 2021 Jan 2.

Authors

Dan Wang¹, Zhouyu Ning², Zhenfeng Zhu², Chenyue Zhang³, Peng Wang², Zhiqiang Meng⁴

Affiliations

¹ Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China.
² Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
³ Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Department of Integrated Therapy, Fudan University Shanghai Cancer Center, Shanghai, China.
⁴ Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. Electronic address: mengzhq@yeah.net.

PMID: 33401010
DOI: 10.1016/j.biocel.2020.105845

Abstract

Phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP), a histidine phosphatase, plays an important role in tumor progression and metastasis as a tumor suppressor. Here, we investigate the effect of LHPP in intrahepatic cholangiocarcinoma (ICC). We discovered that LHPP was downregulated in tumor tissues and low levels of LHPP predicted poor survival. LHPP inhibited ICC cell growth, cell invasion and epithelial-mesenchymal transition (EMT) in vitro and in vivo. Mechanically, LHPP deactivated transforming growth factor‑beta (TGFβ) signaling pathway, and low level LHPP upregulated the expression of TGFβ and phosphorylation of smad2/3. Moreover, inhibition of this pathway reversed the biofunction of LHPP. In summary, these findings demonstrated that LHPP suppressed ICC through inhibiting the activation of TGFβ/smad signaling. Our results indicated that LHPP is a potential therapeutic target in ICC.

Keywords: Epithelial–mesenchymal transition; Intrahepatic cholangiocarcinoma; LHPP; Transforming growth factor‑beta (TGFβ).

MeSH terms

Bile Duct Neoplasms / pathology*
Carcinogenesis
Cell Line, Tumor
Cell Proliferation
Cholangiocarcinoma / pathology*
Epithelial-Mesenchymal Transition
Gene Expression Regulation, Neoplastic
Humans
Inorganic Pyrophosphatase / metabolism*
Signal Transduction*
Smad Proteins / metabolism*
Transforming Growth Factor beta / metabolism*
Up-Regulation

Substances

Smad Proteins
Transforming Growth Factor beta
Inorganic Pyrophosphatase
phospholysine phosphohistidine inorganic pyrophosphate phosphatase, human