Toshihide Akasaka

Loss of Class III β-Tubulin Induced by Histone Deacetylation Is Associated with Chemosensitivity to Paclitaxel in Malignant Melanoma Cells

Overexpression of class III beta-tubulin (TUBB3) is an important mechanism of taxane resistance. Using 7 melanoma cell lines, 2 normal neonatal human epidermal melanocyte (NHEM) cultures, and 49 primary melanomas, we investigated TUBB3 expression, its relationship to chemosensitivity to taxane derivatives, and the epigenetic mechanism controlling TUBB3 gene expression. Normal melanocytes in vitro and in vivo strongly expressed TUBB3 protein. NHEMs exhibited marked chemoresistance to paclitaxel-induced apoptosis. A subset (10 of 49, 20%) of primary malignant melanomas was TUBB3 negative. The incidence of TUBB3-negative melanomas increased with stage of progression. TUBB3 protein expression varied among cell lines; one (HMV-I) of the seven cell lines exhibited an extremely low endogenous level. TUBB3 protein expression correlated well with chemosensitivity to paclitaxel-induced apoptosis (P<0.05). Treatment with a histone deacetylase (HDAC) inhibitor restored TUBB3 expression in HMV-I. Chromatin immunoprecipitation assays revealed that histones H3 and H4 were hypoacetylated at the TUBB3 gene in HMV-I as compared with a TUBB3-overexpressing cell type (HMV-II). Treatment with the HDAC inhibitor induced gain of histone acetylation only in HMV-I. These results suggest that loss of TUBB3 protein may be induced by histone deacetylation in a subset of malignant melanomas, and may be associated with chemosensitivity to taxane.

Drug-Induced Linear IgA Bullous Dermatosis

We report the case of a 69‐year‐old Japanese woman with multiple blistering lesions covering almost her whole body. Linear IgA and C3 depositions were seen at the basement membrane zone on direct immunofluorescence (IF). Linear IgA bullous dermatosis (LABD) is one of the autoimmune diseases resulting in subepidermal blisters. It is clinically similar to bullous pemphigoid and IF is required to distinguish the two diseases. In this case, the blistering lesions appeared after vancomycin treatment. This drug was strongly suspected as a cause of LABD in light of the clinical course of the patient even though a drug‐lymphocyte stimulating test was negative. Among the various implicated causative drugs, vancomycin is the most commonly associated with LABD.

Multiple Basaloid Cell Hamartoma with Alopecia and Autoimmune Disease (Systemic Lupus Erythematosus)

We report a 22‐year‐old Japanese woman with multiple basaloid cell hamartoma with alopecia and autoimmune disease (systemic lupus erythematosus). She presented with infiltrated large annular, brown‐violet, erythematous plaques with atrophic areas in the center on her right cheek, left abdomen and left knee. She also had progressive multiple follicular keratotic papules on her scalp, face, neck, and both axilla and hair loss from her scalp, eyebrow, and axilla. Serologically, reumatoid factor (+++), rheumatoid arthritis hemagglutination test (x1280), and anti‐nuclear antigen (x160) were positive. Histological findings of the annular lesion showed liquefaction degeneration of basal cells, lymphocytic infiltration around hair follicles and capillaries, and panniculitis with lymphoid cell infiltration, which was diagnosed as lupus erythematosus profundus. The histological findings of multiple follicular papular lesions of the scalp and neck showed aggregations of basaloid cells, partially with hair‐bulb‐like structures, which was diagnosed as trichoepithelioma. Taken together, the histogenesis of multiple basaloid cell hamartoma is thought to share the same basis with autoimmune disease.

Downregulation of microRNA-211 is involved in expression of preferentially expressed antigen of melanoma in melanoma cells

MicroRNAs (miRNAs) are small non-coding RNAs whose aberrations are involved in the initiation and progression of human cancers. To seek unique miRNAs contributing to melanoma tumorigenesis, we investigated the global miRNA expression profile of 7 melanoma cell lines and 3 primary cultures of neonatal human epidermal melanocytes (NHEMs) using the stem-loop real-time PCR method. We found 7 miRNAs that were commonly downregulated and 18 that were upregulated in all of the melanoma cell lines in comparison with the 3 primary cultures of NHEMs. We focused on one commonly downregulated miRNA (miR-211), and analyzed its relationship to the expression of preferentially expressed antigen of melanoma (PRAME) protein, which is a potential target of miR-211. We found that all melanoma cell lines exhibited marked down--regulation of miR-211 and upregulation of PRAME mRNA/protein expression in comparison with NHEMs (P<0.05). A significant inverse correlation between miR-211 and PRAME protein expression was found in melanoma cell lines and primary cultures of NHEMs (correlation coefficient of -0.733, P<0.05). We demonstrated that overexpression of miR-211 induced a reduction of PRAME protein levels, and confirmed the target specificity between miR-211 and PRAME by luciferase reporter assay. These results suggest that downregulation of miR-211 may be partly involved in aberrant expression of the PRAME protein in melanoma cells.

Malignant melanoma arising in a sebaceous nevus of the scalp

This is the first report of malignant melanoma arising from sebaceous nevus (SN) of the scalp, although it has been known that various benign and malignant neoplasms may develop in association with SN. After the excisional biopsy for SN with 5 mm free margin, pathological examination revealed the coexistence of nodular melanoma invading to the reticular dermis (IV level of Clark) for a maximal depth of 4 mm. After resection with another 20 mm free margin, there has been no evidence of local recurrence or distant metastasis for nine years.

Trichoblastoma with Rippled‐Pattern

The following is a case study of a 36‐year‐old Japanese man with a trichoblastoma which exhibited a rippled‐pattern on the left temporal region of the scalp. The histological findings of the tumor revealed lobular aggregations composed of immature follicular basaloid cells, lobules of squamous eddy‐like foci of incomplete keratinization or small keratinous cysts, and multiple papillary mesenchymal bodies similar to hair germ. Interestingly, a rippled‐pattern of basaloid cells and hyalinized matrixes resembling the Verocay bodies of neurilemmoma was also observed. We propose that the rippled‐pattern of the basaloid cells and hyalinized matrices is caused by the characteristic stromal induction of trichoblastoma.

Adhesion of peripheral blood mononuclear cells and CD4+ T cells from patients with psoriasis to cultured endothelial cells via the interaction between lymphocyte function‐associated antigen type 1 and intercellular adhesion molecule 1

Background The adhesion of CD4+ T cells to endothelial cells and their subsequent migration to skin tissue are essential to develop the psoriatic skin lesion. However, few studies have examined the role of adhesion molecules in the binding of T cells from patients with chronic plaque psoriasis to endothelial cells in vitro; thus, the adhesion molecules responsible for the development of skin lesions are still unclear.

Cutaneous Mixed Tumor Containing Ossification, Hair Matrix, and Sebaceous Ductal Differentiation

A 58‐year‐old Japanese male presented with a cutaneous mixed tumor containing ossification and hair matrix differentiation on the left side of the chin.

Nucleus Accumbens-Associated 1 Contributes to Cortactin Deacetylation and Augments the Migration of Melanoma Cells

We investigated the prognostic significance and post-transcriptional acetylation-modification of cortactin (CTTN) via the nucleus accumbens-associated 1 (NACC1)-histone deacetylase 6 (HDAC6) deacetylation system in primary melanomas and melanoma cell lines. Overexpression of CTTN protein was observed in 56 (73%) of 77 stage I-IV melanomas, and was significantly correlated with tumor thickness, lymph node metastasis, distant metastasis, and disease outcome. The patients whose tumors exhibited CTTN overexpression had a poorer outcome than patients without this feature (P=0.028, log-rank test). NACC1 and CTTN proteins, but not HDAC6, were overexpressed in four melanoma cell lines in comparison with a primary culture of normal human epidermal melanocytes. Knockdown of both NACC1 and HDAC6 markedly downregulated the migration activity of all melanoma cell lines (P<0.05), and induced a gain of CTTN protein acetylation status. Confocal microscopy showed that hyperacetylation of CTTN modulated by depletion of both NACC1 and HDAC6 induced disappearance of CTTN protein at the leading edge of migrating cells, resulting in stabilization of the focal adhesion structure and development of actin stress fibers. These data suggest that the acetylation status of CTTN modulated by the NACC1-HDAC6 deacetylation system induces acceleration of melanoma cell migration activity via an actin-dependent cellular process, possibly contributing to aggressive behavior (invasion/metastasis) of the melanoma cells.

Two Cases of Basal Cell Carcinoma Arising in Seborrheic Keratosis

The present study reports two cases of basal cell carcinoma arising in seborrheic keratosis. The first case is a seventy‐three‐year‐old female who presented with a blackish nodule arising from a pigmented lesion on her chest. Histopathological analysis of the nodule and the pigmented lesion revealed a basal cell carcinoma with hair follicular differentiation and an acanthotic seborrheic keratosis, respectively. The second case is a seventy‐year‐old female with a blackish nodule arising from a pigmented lesion on her back. Histological analysis of the nodule revealed an atypical basaloid cell mass surrounded by a seborrheic keratosis lesion. In addition to the coexisting seborrheic keratosis with the basal cell carcinoma, a basaloid follicular hamartoma that showed muliple hamartomatous hair follicles or small cysts replaced by a branching cord or lace‐like network of basaloid cells surrounded by fibrovascular stroma was identified. We concluded that both cases presented a rare combination of a seborrheic keratosis which underwent a malignant change to basal cell carcinoma. It appears that both basal cell carcinomas and seborrheic keratosis may derive from a similar source: pluripotential cells of either the epidermis or hair follicle epithelium.