Abstract
Heterogeneous nuclear ribonucleoproteins (hnRNP) are nucleic acid binding proteins involved in RNA processing. We found that hnRNP G is expressed in normal human oral epithelial cells while frequently not found in the cells derived from human oral squamous cell carcinomas (HOSCC). The current study was designed to test the hypothesis that hnRNP G is a tumor suppressor. We investigated the expression levels of hnRNP G protein in normal, precancerous, and malignant oral tissues by in situ immunohistochemistry. In addition, wild-type or mutant hnRNP G was ectopically overexpressed in HOSCC cells and their effects on cellular replication kinetics, colonogenic efficiency, anchorage-independent growth, and in vivo tumorigenicity were determined. In situ immunohistochemical staining showed robust presence of hnRNP G in the basal cell layers of normal oral epithelium but the level of its staining was markedly reduced in dysplastic or cancerous tissues. Ectopic expression of wild-type hnRNP G in cancer cells lacking hnRNP G expression or containing mutant hnRNP G resulted in severe retardation of proliferation, reduction of colonogenic efficiency, loss of anchorage-independent growth, and reduction of in vivo tumorigenicity in immunocompromised mice. In addition, hnRNP G overexpression led to up-regulation of the expression of TXNIP, a cell cycle inhibitory gene, and significantly reduced the expression of the genes that promote cellular proliferation, such as EGR1, JUND, JUNB, FOS, FOSL1, ROS, and KIT. These results indicate that hnRNP G is a tumor suppressor against HOSCC but its mechanisms of action remain to be further investigated.
Highlights
Heterogeneous nuclear ribonucleoproteins are nucleic acid binding proteins involved in RNA processing.We found that hnRNP G is expressed in normal human oral epithelial cells while frequently not found in the cells derived from human oral squamous cell carcinomas (HOSCC)
To determine the association between the expression levels of hnRNP G with HOSCC, we first investigated the expression levels of this protein in normal human oral keratinocytes and five different cancer cell lines (i.e., HEp-2, SCC4, SCC9, SCC15, and Tu-139) derived from HOSCC. hnRNP G expression was readily detectable in normal human oral keratinocytes by Western blotting but was significantly diminished in all tested HOSCC cells, some of which completely lacked the expression (Fig. 1A)
A representative staining pattern is shown in Fig. 1B, which illustrates hnRNP G expression in normal, dysplastic, and cancerous epithelium obtained from a single biopsy specimen
Summary
Heterogeneous nuclear ribonucleoproteins (hnRNP) are nucleic acid binding proteins involved in RNA processing.We found that hnRNP G is expressed in normal human oral epithelial cells while frequently not found in the cells derived from human oral squamous cell carcinomas (HOSCC). Wild-type or mutant hnRNP G was ectopically overexpressed in HOSCC cells and their effects on cellular replication kinetics, colonogenic efficiency, anchorage-independent growth, and in vivo tumorigenicity were determined. HnRNP G was first identified as a nuclear protein with apparent molecular weight of 43 kDa [11, 12] It is composed of 391 amino acid residues encompassing the RNA binding domain (amino acids 10-88) at the NH2 terminus of the protein [11]. This structural feature suggests the physical association of hnRNP G with RNA, which may be required for its role in RNA processing and metabolism [1, 11, 13]. The level of hnRNP G expression and its biochemical activities may have profound and multifaceted effects on the global gene expression profile in cells and maintenance of normal cellular homeostasis
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