Keratin 17 Is Induced in Oral Cancer and Facilitates Tumor Growth.

Keratin subtypes are selectively expressed depending on the cell type. They not only provide structural support, but regulate the metabolic processes and signaling pathways that control the growth of the epithelium. KRT17 (keratin 17) is induced in the regenerative epithelium and acts on diverse signaling pathways. Here, we demonstrate that KRT17 is invariably and permanently induced in oral squamous cell carcinoma (OSCC), as revealed by immunohistochemistry and cDNA microarray analysis. Two representative OSCC cell lines; KRT17-weakly expressing Ca9-22 and KRT17-highly expressing HSC3 were used to establish KRT17-overexpressing Ca9-22 and KRT17-knockdown HSC3 cells. Analysis of these cells revealed that KRT17 promoted cell proliferation and migration by stimulating the Akt/mTOR pathway. KRT17 also upregulated the expression of SLC2A1 (solute carrier family 2 member 1/Glut1) and glucose uptake. To further investigate the effect of KRT17 on tumorigenesis, KRT17-knockout HSC3 cells were established and were transplanted to the cephalic skin of nude mice. The tumors that developed from KRT17-knockout HSC3 cells had a lower Ki-67 labeling index and were significantly smaller compared to the controls. These results indicate that KRT17 stimulates the Akt/mTOR pathway and glucose uptake, thereby facilitating tumor growth. We could not confirm the relationship between KRT17 and SFN (stratifin) in the cells examined in this study. However, our study reinforces the concept that the cellular properties of cancer are regulated by a series of molecules similar to those found in wound healing. In OSCC, KRT17 acts as a pathogenic keratin that facilitates tumor growth through the stimulation of multiple signaling pathways, highlighting the importance of KRT17 as a multifunctional promoter of tumorigenesis.

Expression of basal cell keratin 15 and keratin 19 in oral squamous neoplasms represents diverse pathophysiologies.

Human epithelium contains keratin, which is expressed during differentiation. Depending on the target cell type, different types of keratin are expressed, and their alterations seem to represent changes in cell properties. The basal cells of oral epithelium express keratin 5 (K5), K14, K15 and K19, but their alterations in tumors are unclear. To address this issue and to seek possible diagnostic application, we examined the expression of these keratins in oral squamous cell carcinoma (OSCC) and squamous intraepithelial neoplasm (SIN). cDNA microarray analysis of 43 OSCC revealed slight upregulation of KRT14, downregulation of KRT15 and KRT19, and unaltered KRT5 expression. There were great variations in KRT15 and KRT19 expression across each cancer. Well-differentiated OSCC tended to express more KRT15 and less KRT19 compared to moderately- or poorly-differentiated OSCC. KRT15 was positively correlated with differentiation-related keratin, KRT13. These observations were further investigated by immunohistochemical examination. K5 and K14 were ubiquitously expressed in all 50 OSCC and 50 SIN examined. K15 and K19 were generally downregulated, but were considerably retained in about half of the cases and showed diverse expression patterns. K15-positive cancers tended to show a well-differentiated phenotype, and K19-positive cancers tended to show more invasive tumor fronts. Most K19-positive cancers appeared to develop with little associating SIN. K19 was consistently downregulated in SIN, while K15 was downregulated mainly in high grade SIN. In summary, K15 and K19, unlike K5 or K14, are expressed variably in both SIN and OSCC, which reflects the differences in their pathogenesis and biological behaviors, suggesting their prospective applications as markers for subclassifying OSCC and SIN.

Ectopic production of hair keratin constitutes Rushton's hyaline bodies in association with hematogenous deposits.

A Rushton's hyaline body (HB) is a concretion occasionally found in odontogenic cysts. Unspecified substances produced by the lining epithelium or derived from blood components have been suggested as possible causes of HB formation, but the origin of HBs is still elusive. This study aimed to clarify the origin of HBs. Ten specimens with HBs were obtained from 400 odontogenic cysts. HBs were stained by orcein and Congo red. Immunohistochemical examination revealed that HBs were positive for hair keratin and keratin 17. Hair keratin was concentrated in HBs, and cells with hair keratin expression were hardly seen, while cells with keratin 17 expression were observed near HBs. HBs were also positive for hemoglobin alpha chain. The presence of hair keratin in HBs was confirmed by Western blot analysis. The present study suggests that HBs are formed as a consequence of two independent events: unusual alteration of epithelial differentiation so as to provide hair keratin, and hemorrhage so as to provide erythrocytic substances. Although the ectopic production of hair keratin appears more essential, our results reconcile the long-standing debate between two theories, the keratin theory versus the hematogenous theory, concluding that both substances are required for the genesis of HBs, and also suggesting that they might be novel non-pathological amyloidogenic proteins.