바이러스로부터 보호하는 효소는 암 진화를 촉진할 수 있습니다

Faltas 박사와 그의 팀이 얻은 암세포 핵의 3차원 이미지는 핵(파란색) 내부의 APOBEC3G 단백질(녹색)을 보여줍니다. 신용: 웨일 코넬 의학

바이러스로부터 인간 세포를 방어하는 효소는 암 세포에 무수한 돌연변이를 일으켜 암 진화를 더 큰 악성 종양으로 이끄는 데 도움이 될 수 있다고 연구원들이 주도한 연구에 따르면 웨일 코넬 의학. 이 발견은 효소가 미래의 암 치료를 위한 잠재적 표적이 될 수 있음을 시사합니다.

최근 저널에 발표된 새로운 연구에서 암 연구과학자들은 방광암의 전임상 모델을 사용하여 질병을 촉진하는 APOBEC3G라는 효소의 역할을 조사했으며 그것이 종양 세포의 돌연변이 수를 크게 증가시켜 방광 종양의 유전적 다양성을 높이고 사망률을 앞당기는 것을 발견했습니다.

“우리의 연구 결과는 APOBEC3G가 방광암 진화에 큰 기여를 하고 있으며 향후 치료 전략의 목표로 고려해야 한다는 것을 시사합니다. Weill Cornell Medicine의 세포 및 발달 생물학, NewYork-Presbyterian/Weill Cornell Medical Center의 요로상피암 전문 종양학자입니다.

APOBEC3 계열의 효소는 돌연변이를 일으킬 수 있습니다.[{” attribute=””>RNA or DNA—by chemically modifying a cytosine nucleotide (letter “C” in the genetic code). This can result in an erroneous nucleotide at that position. The normal roles of these enzymes, including APOBEC3G, are to fight retroviruses like HIV—they attempt to hobble viral replication by mutating the cytosines in the viral genome.

The inherent hazardousness of these enzymes suggests that mechanisms must be in place to prevent them from harming cellular DNA. However, starting about a decade ago, researchers using new DNA-sequencing techniques began to find extensive APOBEC3-type mutations in cellular DNA in the context of cancer. In a 2016 study of human bladder tumor samples, Dr. Faltas, who is also director of bladder cancer research at the Englander Institute for Precision Medicine and a member of the Sandra and Edward Meyer Cancer Center, found that a high proportion of the mutations in these tumors were APOBEC3-related—and that these mutations appeared to have a role in helping tumors evade the effects of chemotherapy.

Such findings point to the possibility that cancers generally harness APOBEC3s to mutate their genomes. This could help them not only acquire all the mutations needed for cancerous growth but also boost their ability to diversify and “evolve” thereafter—enabling further growth and spread despite immune defenses, drug treatments, and other adverse factors.

In the new study, Dr. Faltas and his team, including first author Dr. Weisi Liu, a postdoctoral research associate, addressed the specific role of APOBEC3G in bladder cancer with direct cause-and-effect experiments.

APOBEC3G is a human enzyme not found in mice, so the team knocked out the gene for the sole APOBEC3-type enzyme in mice, replacing it with the gene for human APOBEC3G. The researchers observed that when these APOBEC3G mice were exposed to a bladder cancer-promoting chemical that mimics the carcinogens in cigarette smoke, they became much more likely to develop this form of cancer (76% developed cancer) compared with mice whose APOBEC gene was knocked out and not replaced (53% developed cancer). Moreover, during a 30-week observation period, all the knockout-only mice survived, whereas nearly a third of the APOBEC3G mice succumbed to cancer.

To their surprise, the researchers found that APOBEC3G in the mouse cells was present in the nucleus, where cellular DNA is kept using an ‘optical sectioning’ microscopy technique. Previously, this protein had been thought to reside only outside the nucleus. They also found that the bladder tumors of the APOBEC3G mice had about twice the number of mutations compared to the tumors in knockout-only mice.

Identifying the specific mutational signature of APOBEC3G and mapping it in the tumor genomes, the team found ample evidence that the enzyme had caused a greater mutational burden and genomic diversity in the tumors, likely accounting for the greater malignancy and mortality in the APOBEC3G mice. “We saw a distinct mutational signature caused by APOBEC3G in these tumors that is different from signatures caused by other members of the APOBEC3 family,” said Dr. Liu.

Lastly, the researchers looked for APOBEC3G’s mutational signature in a widely used human tumor DNA database, The Cancer Genome Atlas, and found that these mutations appear to be common in bladder cancers and are linked to worse outcomes.

“These findings will inform future efforts to restrict or steer tumor evolution by targeting APOBEC3 enzymes with drugs,” said Dr. Faltas.

Reference: The cytidine deaminase APOBEC3G contributes to cancer mutagenesis and clonal evolution in bladder cancer” by Weisi Liu, Kevin P. Newhall, Francesca Khani, LaMont Barlow, Duy Nguyen, Lilly Gu, Ken Eng, Bhavneet Bhinder, Manik Uppal, Charlotte Récapet, Andrea Sboner, Susan R. Ross, Olivier Elemento, Linda Chelico and Bishoy M. Faltas, 8 December 2022, Cancer Research.
DOI: 10.1158/0008-5472.CAN-22-2912