CPVL promotes glioma progression via STAT1 pathway inhibition through interactions with the BTK/p300 axis.

Hui Yang,Tianbing Chen,Lan Jiang,Xueqin Li,Xiaocen Liu,Mengying Zhang,Xiuming Liang,Mingzhe Ma,Kun Lv,Xiaolong Zhu,Min Zhong

doi:10.1172/jci.insight.146362

Abstract

CPVL (carboxypeptidase, vitellogenic-like) is a serine carboxypeptidase that was first characterized in human macrophages. However, the function of CPVL remains unclear in a variety of tumors. The quantitative PCR (qPCR), Western blotting, and IHC assays were utilized to measure the CPVL expression. CPVL was significantly upregulated in glioma cells and tissues compared with normal cells and tissues, respectively. Moreover, high CPVL expression was correlated with advanced clinical grade and poor prognosis. Silencing of CPVL promoted glioma cell apoptosis, and it inhibited cell proliferation and tumorigenicity in vitro and in vivo. Ingenuity Pathway Analysis (IPA) demonstrated that CPVL silencing activated the IFN-γ/STAT1 signaling pathway, thereby inducing glioma cell apoptosis. Mechanistically, immunopurification, mass spectrometry, IP, and glutathione S-transferase (GST) pull-down experiments elucidated that CPVL physically interacts with Bruton’s tyrosine kinase (BTK) and downregulates the STAT1 phosphorylation through promoting p300-mediated STAT1 acetylation. Our findings reveal the crucial role of CPVL in promoting the progression of glioma through suppressing STAT1 phosphorylation. CPVL might serve as a potential prognostic biomarker and therapeutic target for the treatment of glioma.

Highlights

Glioma is one of the most common types of primary brain tumors in adults and represents one of the most aggressive and lethal human cancer types [1,2,3]
To further screen relevant functional genes, we used the the Cancer Genome Atlas (TCGA) database and the Gene chip, which identified 7 candidate genes, IMPDH1, TMEM98, HIST1H1C, METTL7B, PASK, CPVL, and HILPDA. We evaluated these 7 candidate genes through high-content screening (HCS) analysis, which showed that CPVL silencing significantly inhibited the proliferation of glioma cells (Figure 1, D–F)
Tumorigenesis is a complex multistep process characterized by uncontrolled cell growth, and tumor formation is largely associated with progressive accumulation of genetic and epigenetic alterations in genes or proteins that regulate cell proliferation [35]

Summary

Introduction

Glioma is one of the most common types of primary brain tumors in adults and represents one of the most aggressive and lethal human cancer types [1,2,3]. The World Health Organization (WHO) classifies glioma into 4 grades: I–IV [4]. Despite the advances in early detection, most of the patients are at grade IV glioblastomas (GBM) at the time of diagnosis; the prognosis of these patients remains poor [5, 6]. The median survival period of GBM is only 12–15 months following diagnosis [7]. There are unmet needs for improved therapeutic options for GBM [8]. Dramatic efforts have been put into identifying the molecules that are critical for glioma cell invasion and proliferation, very few were characterized up to date [9,10,11]

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Results

Conclusion