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Objective To detect the expression and localization of Sprouty 2, E-cadherin (E-cad) and Ki-67 in skin tissue of squamous cell carcinoma (CSCC), and to analyze the correlation of Sprouty 2 with E-cad and Ki-67. Methods From March 2018 to July 2018, cancerous tissues (squamous cell carcinoma group), paracancerous tissues (paracancer group), normal skin tissues (case control group) were collected from 15 patients with cephalic and facial CSCC and 10 cases of control normal skin specimens (healthy control group) at Dermatology Hospital of Southern Medical University. Expression and localization of Sprouty 2, E-cad and Ki-67 were detected by qRT-PCR, Western blot and immunohistochemical staining. Results Immunohistochemistry showed that Sprouty 2 was expressed in the keratinocytes and cytoplasm of the whole epidermal layer in all groups. E-cad was expressed in the cell membrane of keratinocytes of all epidermal layers in all groups. Ki-67 was localized in keratinocytes of the basal layer and lower spinous layer in all groups. qRT-PCR and Western blot showed that the mRNA and protein expression in squamous cell carcinoma group were lower than that in paracancer group, case control group and healthy control group (mRNA 0.03±0.03 vs. 0.28±0.36,0.92±0.60, 1.12±0.56; protein 0.68±0.47 vs 1.40±0.72, 1.59±0.86, 1.71±1.28, all P<0.05). E-cad expression levels were lower in squamous cell carcinoma than in other three groups (P<0.05), but Ki-67 was higher than in the other three groups (P<0.05). Correlation analysis showed that the Sprouty 2 was positively correlated with E-cad (r=0.59, P=0.021) and negatively correlated with Ki-67 (r=-0.59, P=0.022). Conclusions Sprouty 2 may be associated with the development of CSCC and play a synergistic role with E-cad in the inhibition of tumor development.