title: Down-regulation of MFG-E8 by RNA interference combined with doxorubicin triggers melanoma destruction.
abstract: The pathogenic mechanism of malignant melanoma involves the dynamic interplay of transformed cell and normal host cell, but cancer treatments always target each partition separately. In the tumor microenvironment, milk fat globule epidermal growth factor-8 (MFG-E8) is a secreted glycoprotein highly expressed in the vertical growth phase of melanoma, leading to tumor progression through coordinated αvβ3 and αvβ5 integrin signaling in tumor cells and host cells. Doxorubicin (Dox) is one of the most widely used antitumor drugs against a lot of solid tumors, including melanoma. In this work, Dox was used to combine with down-regulation of MFG-E8 by RNA interference (RNAi) in order to determine the synergistic effect of the antitumor activity in vivo. And the possible mechanisms were investigated. Results showed that combination group (MFG-E8 RNAi plus Dox) could inhibit the growth of melanoma more effectively than monotherapy or control groups. We found that the combination treatment induced more tumor cell apoptosis and inhibited more neovascularization than other groups. Moreover, this combination treatment attenuated CD4(+) CD25(+) Foxp3(+) Treg cells in tumor-infiltrating lymphocytes compared with other groups. Our findings suggested that MFG-E8 down-regulation enhanced the antitumor function of chemotherapy through coordinated cell apoptosis and immune-mediated mechanisms, which might be a feasible way for cancer therapy.
authors.affiliation: The Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Guo Xue Xiang, No.37, Chengdu, 610041, Sichuan, People's Republic of China.
authors.forename: Jing-Yi
authors.initials: JY
authors.lastname: Zhao
authors.forename: Xue-Lei
authors.initials: XL
authors.lastname: Ma
authors.forename: Zhi-Mian
authors.initials: ZM
authors.lastname: Li
authors.forename: Rui
authors.initials: R
authors.lastname: Deng
authors.forename: Shi-Min
authors.initials: SM
authors.lastname: Wang
authors.forename: Guo-Bo
authors.initials: GB
authors.lastname: Shen
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Feng-Tian
authors.initials: FT
authors.lastname: Wang
authors.forename: Bing-Lan
authors.initials: BL
authors.lastname: Zhang
authors.forename: Yu-Quan
authors.initials: YQ
authors.lastname: Wei
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage*; D000954:Antigens, Surface / Q000235:genetics; D017209:Apoptosis; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D015536:Down-Regulation; D004317:Doxorubicin / Q000008:administration & dosage*; D005260:Female; D055785:Gene Knockdown Techniques; D007111:Immunity, Cellular; D008545:Melanoma / Q000473:pathology / Q000628:therapy*; D008810:Mice, Inbred C57BL; D008894:Milk Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D034622:RNA Interference; D016896:Treatment Outcome
chemical_list: D000903:Antibiotics, Antineoplastic; D000954:Antigens, Surface; C490919:Mfge8 protein, mouse; D008894:Milk Proteins; D004317:Doxorubicin