A novel oncolytic adenovirus selectively silences the expression of tumor-associated STAT3 and exhibits potent antitumoral activity.
Tumor cells acquire the ability to proliferate uncontrollably, resist apoptosis, sustain angiogenesis and evade immune surveillance. Signal transducer and activator of transcription (STAT) 3 regulates all of these processes in a surprisingly large number of human cancers. Consequently, the STAT3 protein is emerging as an ideal target for cancer therapy. This paper reports the generation of an oncolytic adenovirus (M4), which selectively blocks STAT3 signaling in tumor cells as a novel therapeutic strategy. M4 selectively replicated in tumor cells and expressed high levels of antisense STAT3 complementary DNA during the late phase of the viral infection in a replication-dependent manner. The viral progeny yield of M4 in tumor cells was much higher than that of the parent adenoviral mutants, Ad5/dE1A. M4 effectively silenced STAT3 and its target genes in tumor cells while sparing normal cells and exhibited potent antitumoral efficacy in vitro and in vivo. Systemic administration of M4 significantly inhibited tumor growth in an orthotopic gastric carcinoma mouse model, eliminated abdominal cavity metastases and prolonged survival time. In summary, M4 has low toxicity and great potential as a therapeutic agent for different types of cancers.
Han
Zhiqiang
Z
Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
Hong
Zhenya
Z
Chen
Caihong
C
Gao
Qinglei
Q
Luo
Danfeng
D
Fang
Yong
Y
Cao
Yang
Y
Zhu
Tao
T
Jiang
Xuefeng
X
Ma
Quanfu
Q
Li
Wei
W
Han
Lingfei
L
Wang
Daowen
D
Xu
Gang
G
Wang
Shixuan
S
Meng
Li
L
Zhou
Jianfeng
J
Ma
Ding
D
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D003094:Collagen / Q000737:chemistry; D004338:Drug Combinations; D020868:Gene Silencing; D006801:Humans; D007797:Laminin / Q000737:chemistry; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008957:Models, Genetic; D009154:Mutation; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic; D016376:Oligonucleotides, Antisense / Q000235:genetics; D050504:Oncolytic Viruses / Q000235:genetics*; D011509:Proteoglycans / Q000737:chemistry; D050796:STAT3 Transcription Factor / Q000235:genetics*; D015398:Signal Transduction
D000970:Antineoplastic Agents; D004338:Drug Combinations; D007797:Laminin; D016376:Oligonucleotides, Antisense; D011509:Proteoglycans; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C059485:matrigel; D003094:Collagen