ARMS Depletion Facilitates UV Irradiation–Induced Apoptotic Cell Death in Melanoma

Abstract

Tumor cells often aberrantly reexpress molecules that mediate proper embryonic development for advantageous growth or survival. Here, we report that ankyrin repeat-rich membrane spanning (ARMS), a transmembrane protein abundant in the developing and adult neural tissues, is overexpressed in melanoma, a tumor ontogenetically originating from neural crest. Immunohistochemical study of 79 melanocytic lesions showed significantly increased expression of ARMS in primary malignant melanomas (92.9%) and metastatic melanoma (60.0%) in comparison with benign nevocellular nevi (26.7%). To investigate the role of ARMS in melanoma formation, murine B16F0 melanoma cells with stable knockdown of ARMS were established by RNA interference. Downregulation of ARMS resulted in significant inhibition of anchorage-independent growth in soft agar and restrictive growth of melanoma in severe combined immunodeficient mice. Importantly, depletion of ARMS facilitated UVB-induced apoptosis in melanoma cells through inactivation of mitogenactivated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK. Addition of MEK inhibitor PD98059 further sensitized ARMS-depleted melanoma cells to UVBinduced apoptosis, whereas constitutively active MEK rescued ARMS-depleted cells from apoptosis. We further showed that BRAF, a downstream signaling molecule of ARMS in ERK pathway, is not mutated as a constitutively active form in acral lentiginous melanoma; in contrast, BRAF T1799A mutation, which leads to constitutive activation of ERK signaling, was detected in 57.1% of superficial spreading melanoma. Our study suggests that overexpression of ARMS per se serves as one mechanism to promote melanoma formation by preventing stress-induced apoptotic death mediated by the MEK/ERK signaling pathway, especially in acral lentiginous melanoma, most of which does not harbor BRAF mutation. [Cancer Res 2007;67(24):11547-56]

Differentiating intratumoral melanocytes from Langerhans cells in nonmelanocytic pigmented skin tumorsin vivoby label-free third-harmonic generation microscopy

“…Immunohistochemistry was performed as previously described. 36 Diaminobenzidine (DAB; Agilent Technologies, Dako, Denmark) was applied for colorization and the slides were counterstained for nuclei with hematoxylin. The sections were examined double blindly by two pathologists.…”

Investigating the role of ankyrin-rich membrane spanning protein in human immunodeficiency virus type-1 Tat-induced microglia activation

“…In addition, ARMS expression was detected in neuroblastoma tumors and found to mediate stabilization of neurotrophin signaling providing survival advantages (Rogers and Schor, 2013). Earlier, Liao et al, 2007 demonstrated higher levels of ARMS in primary and metastatic melanoma as compared to benign melanoma cases. Furthermore, depletion of ARMS in a murine melanoma cell line (B16F0) resulted in inhibition of growth in soft agar as well as growth of melanoma in severe combined immunodeficient mice.…”

MiR-4638-5p inhibits castration resistance of prostate cancer through repressing Kidins220 expression and PI3K/AKT pathway activity

“…Although most of the above cellular features are associated with cancer development and progression, research of Kidins220 in human malignancies is very limited. Kidins220 overexpression has been reported in melanoma and it has been shown to contribute to tumor formation by activating MEK/ERK signaling pathway and consequently preventing transformed melanocytes from the stress-induced apoptosis [61]. Expression of Kidins220 has also been reported in neuroblastoma tumours, where it stabilizes nerve growth factor-induced survival signalling through MAPK/ERK signalling [62].…”