title: 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. Down-regulation 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 mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK. Addition of MEK inhibitor PD98059 further sensitized ARMS-depleted melanoma cells to UVB-induced 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.
authors: Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors: Yi-Hua
authors: YH
authors: Liao
authors: Su-Ming
authors: SM
authors: Hsu
authors: Pei-Hsin
authors: PH
authors: Huang
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D052816:Foreskin; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008544:Melanocytes / Q000166:cytology / Q000502:physiology; D008545:Melanoma / Q000473:pathology / Q000503:physiopathology*; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000502:physiology*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D014466:Ultraviolet Rays
chemical_list: C482591:KIDINS220 protein, human; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf