A loss of profilin‐1 in late‐stage oral squamous cell carcinoma

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PFN1 is a member of the profilin family of small proteins (12–15 Kda), which have the ability to bind actin and affect its polymerization and cytoskeletal growth that effects cell locomotion, cell shape, and cell transport 1. The protein is found extracellularly in saliva and in dental crevicular fluid, among other places 3, but it functions chiefly inside cells 1. The ability of the protein to promote actin polymerization originally suggested the primary function was to regulate cell motility, but it is now clear that PFN1, like other profilins, can interact with additional proteins, including the phosphoinositides and polyproline‐containing proteins, which may allow it to regulate multiple pathways 1. These interactions can affect cell signaling, membrane trafficking, and cell cycle arrest. PFN1 is also absolutely necessary for cytokinesis 6 and cell proliferation; however, enrichment of the protein in cell lines impairs cell motility and promotes apoptosis 7. These latter two observations are consistent with the protein being a tumor suppressor. Indeed, PFN1 is downregulated overall or at least in late‐stage breast, pancreatic, laryngeal, and bladder cancers 7. In bladder cancer, for example, epithelial cancer expression of PFN1 decreases with worsening prognosis, while stromal levels increase 13. Thus, loss of the protein seems to correlate with advanced tumors in at least some tumor types. Because of multiple protein interactions with PFN1, it is expected that many pathways are regulated; however, a clear mechanism for multiple functions in different cell types remains unclear. There is also evidence that changes in PFN1 levels and cell localization play an important role in some tumor types 5. In short, the protein seems to have context‐dependent effects on cell motility and on multiple pathways that can contribute to transformation though a tumor suppressor function.
TMSB4 is found at high levels in saliva in adults and even higher levels in neonatal saliva, which seems to indicate high expression in at least some tissues of the oral cavity. TMSB4 is the most abundant form of the multifunctional beta‐thymosin proteins that include TMB4, B10, and B15. The 43 amino acid TMB4 protein is believed to be the main actin‐sequestering protein, and there is evidence that it plays a role in regulating cell motility. In addition, the protein has roles in influencing angiogenesis, inflammation, cell survival, wound healing, and calcium deposition 14. There is evidence that TMSB4, a protein expressed at high levels in embryonic tissues, plays a role in expression of stem cell properties, and it is postulated that enrichment in some tumor types is linked to acquisition of embryonic cell properties or metastasis and tissue invasion. For example, TMSB4 is linked to metastatic spread of various malignancies, such as colorectal and breast 15 although enhanced expression most significantly occurs on the cancer border in stromal tissue and not in tumor cells themselves. In fact, in hepatocellular carcinoma, TMSB4 has been noted to be poorly expressed in the majority of tumor tissue while easily detected in normal parenchyma. Additionally, the protein is totally absent in hepatocellular tumor cells undergoing stromal invasion 15. In general, its expression seems to counter differentiation, and because TMSB4 is found at elevated levels in several tumor types, it is thought to work as an oncogene but its effects are also likely related to an altered stromal microenvironment 17.
We used brush oral cytology to ascertain variability of the mRNAs encoding PFN1 and TMSB4 proteins between different OSCC tumors. If these proteins closely linked to tumor progression vary on the RNA level in OSCC epithelium, we reckoned that they may also vary on the protein level.
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