Nicotinic acetylcholine receptor of α7 type (α7-nAChR) is a ligand-gated ion channel composed of five identical α7 subunits. Secreted Ly6/uPAR-related protein-1 (SLURP-1) controls carcinoma progression by negative modulation of oncogenic α7-nAChR. In this study, we observed dramatic decrease of SLURP-1 plasma level in patients with metastatic melanoma. We suggested usage of recombinant analog of human SLURP-1 (rSLURP-1) to compensate this deficiency for metastatic melanoma treatment. rSLURP-1 did not affect viability of different patient-derived metastatic melanoma cells, but reduced migration of some of them. Metastatic melanoma cells of other lines were resistant to rSLURP-1. Antimigratory rSLURP-1 effect was mediated by α7-nAChR, while resistance to rSLURP-1 correlated with overexpression of human-specific gene, which encodes the α7 subunit with truncated -terminal region (dupα7) able to form hybrid α7/dupα7-nAChR channels. Electrophysiological study in oocytes showed that rSLURP-1 inhibits α7/dupα7-nAChR weaker than α7-nAChR. In contrast, 'Oncotag' peptide, which mimics the loop I of SLURP-1, inhibited α7/dupα7- and α7-nAChRs with similar efficiency. Oncotag suppressed metastatic melanoma cell migration independently on dupα7 expression. Computer modeling provided rationale for altered activities of rSLURP-1 and Oncotag on α7/dupα7-nAChR. TCGA database analysis revealed correlation between and gene expression and worse survival prognosis for patients with metastatic melanoma. Thus, (1) low plasma SLURP-1 level may be a specific marker of metastatic melanoma development, (2) metastatic melanoma progression can be controlled by α7-nAChR inhibition, and (3) dupα7 overexpression is a new molecular mechanism of melanoma resistance to internal cholinergic control and new target for melanoma treatment.