Selective targeting of HPV-16 E6/E7 in cervical cancer cells with a potent oncolytic adenovirus and its enhanced effect with radiotherapy in vitro and vivo.
Recent studies have shown that oncolytic adenovirus specifically targeted tumor cells while sparing normal cells. Here, we report a novel E1A-mutant adenovirus (M6) with antisense HPV16 E6 E7 DNA inserted into the deleted 6.7K/gp19K region of E3. The target effects of M6 on HPV16-positive cervical cancer cells were evaluated in vivo and in vitro. By using cytopathic effect (CPE) and viral replication assays, we verified M6 was competent to selectively replicate in cervical cancer cells in vitro. Moreover, we found infection of M6 was able to inhibit the expression of HPV16 E6 and E7 oncogenes and induce apoptosis of HPV16-positive cervical cancer cells. Further analysis in vitro revealed that the invasive ability of SiHa cells was significantly inhibited by M6. To determine if M6 synergized with radiotherapy-induced anti-tumor activity against HPV16-related cancer cells, we transfected SiHa cells with M6 followed by a single exposure to radiation. A significantly suppression of cell growth and induced apoptosis was observed in SiHa cells received M6 transfection combined with radiotherapy. Animal experiments showed that M6 transfection notably improved the survival of tumor-bearing mice in combination with radiotherapy, much superior to that of those treated by Adv5/dE1A plus radiation or M6 alone. These findings indicated the anti-tumoral efficacy of M6 on HPV16-positive cervical cancer cells and its synergic therapeutic application in radiation for cervical cancer.
Wang
Wei
W
Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China.
Sima
Ni
N
Kong
Debo
D
Luo
Aiyue
A
Gao
Qinglei
Q
Liao
Shujie
S
Li
Wei
W
Han
Lingfei
L
Wang
Juan
J
Wang
Shixuan
S
Lu
Yunping
Y
Wang
Daowen
D
Xu
Gang
G
Zhou
Jianfeng
J
Meng
Li
L
Ma
Ding
D
D000256:Adenoviridae / Q000235:genetics* / Q000502:physiology; D017500:Adenovirus E1A Proteins / Q000235:genetics; D000818:Animals; D016375:Antisense Elements (Genetics); D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness; D009856:Oncogene Proteins, Viral / Q000037:antagonists & inhibitors* / Q000235:genetics; D050130:Oncolytic Virotherapy; D050725:Papillomavirus E7 Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D002583:Uterine Cervical Neoplasms / Q000628:therapy*; D014779:Virus Replication
D017500:Adenovirus E1A Proteins; D016375:Antisense Elements (Genetics); C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16