Theranostics 2019; 9(5):1453-1473. doi:10.7150/thno.29987

Research Paper

Oncogenic MSH6-CXCR4-TGFB1 Feedback Loop: A Novel Therapeutic Target of Photothermal Therapy in Glioblastoma Multiforme

Yaodong Chen1, Pengfei Liu2, Peng Sun2, Jian Jiang1, Yuanbo Zhu2, Tianxiu Dong1, Yingzhe Cui2, Yuan Tian2, Tingting An1, Jiuwei Zhang1, Zizhuo Li1✉, Xiuhua Yang1✉

1. Department of Abdominal Ultrasonography, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
2. Department of Magnetic Resonance, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China

Abstract

Glioblastoma multiforme (GBM) has been considered the most aggressive glioma type. Temozolomide (TMZ) is the main first-line chemotherapeutic agent for GBM. Decreased mutS homolog 6 (MSH6) expression is clinically recognized as one of the principal reasons for GBM resistance to TMZ. However, the specific functions of MSH6 in GBM, in addition to its role in mismatch repair, remain unknown.

Methods: Bioinformatics were employed to analyze MSH6 mRNA and protein levels in GBM clinical samples and to predict the potential cancer-promoting functions and mechanisms of MSH6. MSH6 levels were silenced or overexpressed in GBM cells to assess its functional effects in vitro and in vivo. Western blot, qRT-PCR, and immunofluorescence assays were used to explore the relevant molecular mechanisms. Cu2(OH)PO4@PAA nanoparticles were fabricated through a hydrothermal method. Their MRI and photothermal effects as well as their effect on restraining the MSH6-CXCR4-TGFB1 feedback loop were investigated in vitro and in vivo.

Results: We demonstrated that MSH6 is an overexpressed oncogene in human GBM tissues. MSH6, CXCR4 and TGFB1 formed a triangular MSH6-CXCR4-TGFB1 feedback loop that accelerated gliomagenesis, proliferation (G1 phase), migration and invasion (epithelial-to-mesenchymal transition; EMT), stemness, angiogenesis and antiapoptotic effects by regulating the p-STAT3/Slug and p-Smad2/3/ZEB2 signaling pathways in GBM. In addition, the MSH6-CXCR4-TGFB1 feedback loop was a vital marker of GBM, making it a promising therapeutic target. Notably, photothermal therapy (PTT) mediated by Cu2(OH)PO4@PAA + near infrared (NIR) irradiation showed outstanding therapeutic effects, which might be associated with a repressed MSH6-CXCR4-TGFB1 feedback loop and its downstream factors in GBM. Simultaneously, the prominent MR imaging (T1WI) ability of Cu2(OH)PO4@PAA could provide visual guidance for PTT.

Conclusions: Our findings indicate that the oncogenic MSH6-CXCR4-TGFB1 feedback loop is a novel therapeutic target for GBM and that PTT is associated with the inhibition of the MSH6-CXCR4-TGFB1 loop.

Keywords: glioblastoma multiforme, MSH6-CXCR4-TGFB1 feedback loop, photothermal therapy, magnetic resonance imaging, Cu2(OH)PO4

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How to cite this article:
Chen Y, Liu P, Sun P, Jiang J, Zhu Y, Dong T, Cui Y, Tian Y, An T, Zhang J, Li Z, Yang X. Oncogenic MSH6-CXCR4-TGFB1 Feedback Loop: A Novel Therapeutic Target of Photothermal Therapy in Glioblastoma Multiforme. Theranostics 2019; 9(5):1453-1473. doi:10.7150/thno.29987. Available from http://www.thno.org/v09p1453.htm