Porf-2 Inhibits Tumor Cell Migration Through the MMP-2/9 Signaling Pathway in Neuroblastoma and Glioma

Abstract

Tumor migration and invasion are key pathological processes that contribute to cell metastasis as well as treatment failure in patients with malignant tumors. However, the mechanisms governing tumor cell migration remain poorly understood. By analyzing the tumor-related database and tumor cell lines, we found that preoptic regulatory factor-2 (Porf-2) is downexpressed in both neuroblastoma and glioma. Using in vitro assays, our data demonstrated that the expression of Porf-2 inhibits tumor cell migration both in neuroblastoma and glioma cell lines. Domain-mutated Porf-2 plasmids were then constructed, and it was found that the GAP domain, which plays a role in the inactivation of Rac1, is the functional domain for inhibiting tumor cell migration. Furthermore, by screening potential downstream effectors, we found that Porf-2 can reduce MMP-2 and MMP-9 expression. Overexpression of MMP-2 blocked the inhibitory effect of Porf-2 in tumor cell migration both in vitro and in vivo. Taken together, we show for the first time that Porf-2 is capable of suppressing tumor cell migration via its GAP domain and the downregulation of MMP-2/9, suggesting that targeting Porf-2 could be a promising therapeutic strategy for nervous system tumors.

Anti-Tumor Mechanisms Associated With Regulation of Non-Coding RNA by Active Ingredients of Chinese Medicine: A Review

“…Matrix metalloproteinases (MMPs) play important roles in mediating angiogenesis, metastasis, and invasion. MMP-2/9 expression is related to the progression of many tumors, such as colon cancer ( 83 ), neuroblastoma ( 84 ), and bladder cancer ( 85 ). Paeoniflorin regulated miR-16/29b, which targeted MMP-9/2 ( 56 ) to inhibit the growth and invasion of multiple myeloma cells ( 57 ).…”

Functional analysis of N-acetylglucosaminyltransferase-I knockdown in 2D and 3D neuroblastoma cell cultures

“…Overexpression of matrix metalloproteinases (MMP), paladin, and vimentin are linked to modified cell morphology and invasiveness in cancer cells [9][10][11]. MMPs increase the availability of growth factors and cytokines to receptor tyrosine kinases (RTKs) by degrading the extracellular matrix [12].…”

MMP-9 Reinforces Radiation-Induced Delayed Invasion and Metastasis of Surviving Neuroblastoma Cells Through Second-Signaling Positive Feedback With NFkB Via Both ERK and IKK Activation

“…The hemopexin-like domain is critical for speci city during recognition and interacts with gelatin and collagen (Roeb et al 2002) About two decades ago, production of MMP9 by NB cells; its role in induced angiogenesis, tumor progression, and metastasis; and association of MMP9 with advanced disease stage and poor clinical outcomes were documented (Sugiura et al 1998;Ribatti et al 1998;Ara et al 1998). Since then, a growing number of studies have reiterated the role of MMP9 in NB progression and poor clinical outcomes with the recognition of mechanisms and cellular functions involved (Li et al 2020;Sans-Fons et al 2010;Cheng et al 2005). Consistently, global efforts were focused on identifying lead therapeutic deliverables that could target activated MMP9 signaling in NB (Li et al 2020;Xu et al 2019;Farabegoli et al 2018).…”

“…Since then, a growing number of studies have reiterated the role of MMP9 in NB progression and poor clinical outcomes with the recognition of mechanisms and cellular functions involved (Li et al 2020;Sans-Fons et al 2010;Cheng et al 2005). Consistently, global efforts were focused on identifying lead therapeutic deliverables that could target activated MMP9 signaling in NB (Li et al 2020;Xu et al 2019;Farabegoli et al 2018). Conversely, studies from our lab and others have showed therapeutic pressure-associated acquired molecular rearrangements, clonal selection, and cellular function, leading to drug resistance, NB evolution, and poor outcomes (Somasundaram et al 2019;Aravindan et al 2013b).…”