Targeting hypoxia-inducible factor-1alpha with Tf-PEI-shRNA complex via transferrin receptor-mediated endocytosis inhibits melanoma growth.
Malignant melanoma (MM) is a major public health problem. The development of effective, systemic therapies for MM is highly desired. We showed here that the transferrin receptor (TfR) was a suitable surface marker for targeting of gene therapy in MM and that the hypoxia-inducible factor-1alpha (HIF-1alpha) was an attractive therapeutic molecular target in MM. We observed that inhibition of HIF-1alpha blocked cell proliferation and induced cell apoptosis in vitro. We then showed that a transferrin-polyethylenimine-HIF-1alpha-short-hairpin RNA (Tf-PEI-HIF-1alpha-shRNA) complex could target MM specifically and efficiently both in vivo and in vitro, exploiting the high expression of the TfR in MM. The systemic delivery of sequence-specific small-interfering RNA (siRNA) against HIF-1alpha by the Tf- PEI-HIF-1alpha-shRNA complex dramatically inhibited tumor growth in the A375 MM xenograft model. The underlying concept of transfecting a HIF-1alpha shRNA expression vector complexed with Tf-PEI to block HIF-1alpha holds promise as a clinical approach to gene therapy for MM.
Liu
Yeqiang
Y
Department of Dermatology, Hospital Affiliated to Medical College of JiuJiang University, JiuJiang, People's Republic of China.
Tao
Juan
J
Li
Yan
Y
Yang
Jing
J
Yu
Yan
Y
Wang
Min
M
Xu
Xiaoyuan
X
Huang
Changzheng
C
Huang
Wei
W
Dong
Jing
J
Li
Li
L
Liu
Jing
J
Shen
Guanxin
G
Tu
Yating
Y
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D004705:Endocytosis / Q000235:genetics / Q000502:physiology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000502:physiology*; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008297:Male; D008545:Melanoma / Q000628:therapy*; D051379:Mice; D011094:Polyethyleneimine / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000737:chemistry* / Q000235:genetics* / Q000502:physiology; D011990:Receptors, Transferrin / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014168:Transferrin / Q000737:chemistry*
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; D011990:Receptors, Transferrin; D014168:Transferrin; D011094:Polyethyleneimine