UNC93B1 promotes tumoral growth by controlling the secretion level of granulocyte macrophage colony-stimulating factor in human oral cancer
Introduction
The Unc-93 gene was first reported to regulate muscle contraction and served as the regulatory subunit of the potassium channel complex in Caenorhabditis elegans. Unc-93 contains a highly charged 245-amino acid N-terminal domain followed by five to 10 putative transmembrane domains. Unc-93 is a member of a multigene family that is conserved in C. elegans, Drosophila, and mammals [1]. Two paralogues of Unc-93, i.e., UNC93A and UNC93B, are highly conserved between humans and mice [2].
UNC93A, a protein with 12 transmembrane helixes, is expressed in the brain and peripheral tissues and responds to nutrient availability by regulating genes involved in murine metabolic processes [3]. There are four isoforms of the UNC93B genes, i.e., UNC93B1, UNC93B2, UNC93B3, and UNC93B4. Of the UNC93B isoforms, UNC93B2, UNC93B3, and UNC93B4 are non-functional genes or pseudogenes [4]. UNC93B1, a nucleotide-sensing protein signaling regulator, has an important role in the trafficking of the proteins from the endoplasmic reticulum to the endolysosomes [3]. Nucleotide-sensing proteins are the key components of the innate immune system that recognize conserved sequences on the surface of pathogens and trigger a host defense response [5]. Therefore, UNC93B1 is correlated with immune diseases, such as influenza, herpes simplex encephalitis, and systemic lupus erythematosus; however, the role of UNC93B1 in cancers including human oral squamous cell carcinomas (OSCCs) remains unknown [[6], [7], [8]].
The current study shows that UNC93B1 is overexpressed in OSCCs in vitro and in vivo and that UNC93B1 enhances proliferation of OSCCs by promoting cell-cycle progression.
Section snippets
Ethics statement
The Ethics Review Board of Chiba University approved the study protocol (protocol number, 680). All patients provided written informed consent before study entry.
Cells and clinical OSCC tissue samples
In addition to nine OSCC-derived cell lines, described in previous studies [[9], [10], [11], [12]], we used HSC-3-M3, which was obtained from the Japanese Collection of Research Bioresources Cell Bank (Ibaraki, Osaka, Japan). Primary cultured human normal oral keratinocytes (HNOKs), which were used as normal controls, were collected
Overexpression of UNC93B1 in OSCC cells
The mRNA and protein expression status of UNC93B1 in the 10 OSCC-derived cell lines were evaluated using qRT-PCR and immunoblot analyses, respectively. All cells showed significant up-regulation (p < 0.05) of UNC93B1 mRNA compared with the HNOKs (Fig. 1A). The UNC93B1 protein also was up-regulated in all OSCC cells compared with the HNOKs (Fig. 1B).
Evaluation of UNC93B1 expression in primary OSCCs
Representative IHC results, which show staining of UNC93B1 in normal oral tissue and primary OSCC (×200 magnification), are shown in Fig. 1C.
Discussion
UNC93B1 overexpression was correlated significantly (p < 0.05) with tumoral size, and the UNC93B1 knockdown cells showed decreased cellular proliferation by cell-cycle arrest at the G1 phase with up-regulation of p21Cip1 and down-regulation of CDK4, CDK6, cyclin D1, and cyclin E (Fig. 2E), indicating that UNC93B1 is highly involved in tumoral growth in OSCCs.
Since UNC93B1 controls production of some secretion proteins [36], we speculated that UNC93B1 regulates the expression of growth factors
Conflicts of interest
The authors have no financial relationships to disclosure.
Acknowledgments
We thank Ms. Lynda C. Charters for editing this manuscript. The authors received no financial support.
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