TRIM29 (tripartite motif-containing protein 29) is a TRIM family protein that has been implicated in breast, colorectal, and pancreatic cancers. However, its role in stratified squamous epithelial cells and tumors has not been elucidated.Here, we investigate the expression of TRIM29 in cutaneous head and neck squamous cell carcinomas (SCC) and its functions in the tumorigenesis of such cancers. TRIM29 expression was lower in malignant SCC lesions than in adjacent normal epithelial tissue or benign tumors. Lower expression of TRIM29 was associated with higher SCC invasiveness. Primary tumors of cutaneous SCC showed aberrant hypermethylation of TRIM29. Depletion of TRIM29 increased cancer cell migration and invasion; conversely, overexpression of TRIM29 suppressed these. Comprehensive proteomics and immuno-precipitation analyses identified keratins and keratin-interacting protein FAM83H as TRIM29 interactors. Knockdown of TRIM29 led to ectopic keratin localization of keratinocytes. In primary tumors, lower TRIM29 expression correlated with the altered expression of keratins. Our findings reveal an unexpected role for TRIM29 in regulating the distribution of keratins, as well as in the migration and invasion of SCC. They also suggest that the TRIM29-keratin axis could serve as a diagnostic and prognostic marker in stratified epithelial tumors and may provide a target for SCC therapeutics.Significance: These findings identify TRIM29 as a novel diagnostic and prognostic marker in stratified epithelial tissues. Cancer Res; 78(24); 6795-806. Ó2018 AACR.

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Pazopanib is a potent and selective multi-targeted tyrosine kinase inhibitor that has been reported to extend progression-free survival in cases of metastatic soft-tissue sarcoma. However, the efficacy of pazopanib for cutaneous angiosarcoma has not been confirmed. We report eight cases of angiosarcoma treated with pazopanib, and review the efficacy and safety of pazopanib therapy. We retrospectively investigated the clinical information, including age, sex, body surface area, location, performance status, lung or pleural metastasis, preceding treatment, oral dose of pazopanib, response rate, progression-free survival and adverse effects. Five of the eight patients needed to stop the pazopanib treatment due to severe adverse effects, including thrombocytopenia, anemia, drug-associated pancreatitis, acute fulminant hepatitis and general fatigue. Progression-free survival ranged 0.5-3.5 months (mean ± standard deviation, 1.81 ± 1.03). Overall survival ranged 3-26 months (14.13 ± 9.47). Six of the eight cases showed progressive disease, and two of the eight cases showed stable disease. To assess overall survival in angiosarcoma treated with pazopanib, we compared the pazopanib-treated group (n = 8) with the non-pazopanib-treated control group (n = 10). There was no significant difference between two groups (P = 0.19, log-rank test). In conclusion, our case series suggests that pazopanib does not bring remarkable improvement in patients with angiosarcoma.

EditorIt is sometimes hard to clinically distinguish seborrheic keratosis (SK) from other skin tumours, for example, pigmented basal cell carcinoma, actinic keratosis, keratoacanthoma and nevus pigmentosus, especially when the dermoscopic findings are atypical for SK. It is our experience that, in SK cases with such atypical findings, a surgical specimen will often show irritated seborrheic keratosis (ISK). No reports have addressed dermoscopic features of ISK.We studied the lesions of 10 patients, all cases histopathologically diagnosed as ISK at the Hokkaido University Hospital from 2009 to 2014, in order to contrast the dermoscopic and histopathological findings. Our team of dermatological experts retrospectively investigated the clinical and dermoscopic findings in each case. Dermoscopic examinations were done under a non-polarized light source with a gel interface and direct contact (Derma 9500, Derma Medical Inc., Japan). We investigated each histopathological finding under haematoxylin and eosin staining in detail, according to the histopathological findings of pseudohorn cysts, keratotic plugs, parakeratosis/papillary acanthosis, dilated vessels, squamous cells and vessel shapes. The patients' clinical information, dermoscopic features and histopathological findings are shown in Table 1. In the result, the dermoscopic findings of ISK tend to show the low frequency of comedo-like openings and of multiple milia-like cysts, and show small pinkish round structures on a whitish background. The 'small pinkish round structures on a whitish background' in dermoscopic examination might be a feature specific to irritated seborrheic keratosis. This unique structure is histopathologically reflected as dilated vessels and surrounding acanthosis of tumour cells (arrowhead Fig. 1).The characteristic feature of ISK is the presence of 'squamous cells', numerous eddies composed of eosinophilic, flattened squamous cells arranged in an onion-peel fashion and resembling poorly differentiated horn pearls. In addition, ISK may show areas of downward proliferation breaking through the horizontal demarcation generally present in non-irritated SK. Beneath ISK lesions, the inflammation tends to be mild or absent, indicating that ISK is different from inflamed SK. Our present ISK study showed two trend findings: ISK tends not to reveal typical dermoscopic features of SK and ISK presents 'small pinkish round structures on a whitish background'.We speculate that this condition can be attributed to the histopathological features of ISK. ISK tumour cells mainly consist of poorly keratinized squamous cells. This might be why pseudohorn cysts and keratotic plaques are not frequently observed histologically in number and size. Furthermore, due to the high severity of acanthosis, it was hard to detect small histological changes by dermoscopic examination: therefore, ISK is not similar to reveal typical dermoscopic features of SK, including milia-like cysts or comedo-like openings.5 In addition, there were relatively abundant dilated vessel...

Cutaneous squamous cell carcinoma (SCC) is one of the common cancers in Caucasians, accounting for 20–30% of cutaneous malignancies. The risk of metastasis is low in most patients; however, aggressive SCC is associated with very high mortality and morbidity. Although cutaneous SCC can be treated with surgical removal, radiation and chemotherapy singly or in combination, the prognosis of patients with metastatic SCC is poor. Recently, the usage of immune checkpoint blockades has come under consideration. To develop effective therapies that are less toxic than existing ones, it is crucial to achieve a detailed characterization of the molecular mechanisms that are involved in cutaneous SCC pathogenesis and to identify new drug targets. Recent studies have identified novel molecules that are associated with SCC carcinogenesis and progression. This review focuses on recent advances in molecular studies involving SCC tumor development, as well as in new therapeutics that have become available to clinicians.

Our results reveal a crucial function for Drp1 in regulating tumor growth, mitochondrial morphology, and cell cycle in cutaneous SCC, suggesting that Drp1 could be a novel target for skin tumor therapies.