Down-regulation of MFG-E8 by RNA interference combined with doxorubicin triggers melanoma destruction.

Zhao, Jing-yi; Ma, Xue-lei; Li, Zhi-mian; Deng, Rui; Wang, Shi-min; Shen, Guo-bo; Zhang, Jing; Wang, Feng-tian; Zhang, Bing-lan; Wei, Yu-quan

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 αβ and αβ 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.

DOWNREGULATION; EPIDERMAL growth factor; MILKFAT; RNA interference; DOXORUBICIN; ANTINEOPLASTIC agents; MELANOMA treatment; CANCER invasiveness

Clinical & Experimental Medicine, 2015, Vol 15, Issue 2, p127

1591-8890

Academic Journal

10.1007/s10238-014-0277-6