In This Article
- The exact etiology of cervical cancer is unknown, but contrary to previous understanding, new research finds that human papillomavirus (HPV) infection is not "a necessary step" for cervical carcinogenesis
- New data show YAP1 oncogene hyperactivation alone can drive cervical carcinogenesis
- When YAP1 hyperactivation combines with HPV infection, the synergy accelerates initiation and progression of cervical carcinogenesis
- Vaccination for HPV remains critical for protecting the health of sexually active patients
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According to the National Cervical Cancer Coalition, more than 13,500 women are diagnosed with cervical cancer each year in the United States and it is the most common gynecological cancer in the world. The World Health Organization reports that it is the fourth leading cause of cancer-related death in women, worldwide. However, despite its prevalence, the etiology of cervical cancer is still not well understood and there is an urgent need to fully understand how the disease develops.
Persistent infection with human papillomavirus (HPV) has been implicated in the development of cervical cancer, even years post-infection. However, new research led by Cheng Wang, PhD, an associate investigator at the Vincent Center for Reproductive Biology in the Department of Obstetrics & Gynecology at Massachusetts General Hospital, suggests that this factor alone is not sufficient. Data from Dr. Wang's work suggest an evolving role for the YAP1 oncogene in cervical cancers, revealing an unconventional carcinogenesis mechanism.
YAP1, HPV and Cervical Cancer
More than 70% of all sexually active women are infected with HPV, but fewer than 1% of those actually develop cancer. This asymmetry suggests more factors are involved in the progression of cervical cancer. In particular, Dr. Wang notes that the skew between infection rate and disease prevalence indicates a role for individual genetic susceptibility.
"People were thinking you have to get HPV for cervical cancer to develop," says Dr. Wang. "But we suspected that wasn't true because we found that hyperactivation of YAP1 protein alone can induce cervical cancer in a mouse model. HPV doesn't need to be present, so we began thinking that the disrupted Hippo/YAP1 signaling is one of the most important intrinsic factors that contribute to cervical carcinogenesis."
Hyperactive YAP1 Synergizes with HPV
A recent study from Dr. Wang's team demonstrated that hyperactivation of YAP1 determines individual susceptibility to HPV infection and the initiation and progression of cervical cancer.
Their mechanistic study included in vitro and in vivo animal model research. Detailed findings supporting the conclusions that:
- Hyperactivation of YAP1 in cervical epithelial cells facilitated HPV infection
- By synergizing with HPV, the YAP1 hyperactivation increases the putative HPV receptor molecules
- The combined effects of HPV and YAP1 disrupt host cell innate immunity and weaken the defense against cancer of the cervix
In addition, by analyzing the genomic data from tissues of 191 patients, they found that the upstream tumor-suppressor genes of the Hippo/YAP signaling pathway, such as FAT1/2/3/4 and LATS1/2, are frequently deleted or mutated, while the downstream oncogenes such as YAP1 and WWTR1, are amplified and upregulated in the cervical cancer patients. These observations suggest that the disrupted Hippo/YAP signaling pathway likely plays a role in human cervical carcinogenesis and is associated with poor outcomes.
"Our study reveals an unconventional mechanism for cervical carcinogenesis," says Dr. Wang.
While there is more to be understood about the relationship between HPV, YAP1 and the development of cervical cancer, Dr. Wang envisions clinical applications of the team's work in the realm of personalized medicine to target the patients most susceptible to cervical cancer.
When translated and applied to human cancers, the team's research could result in a multimodal targeted strategy that focuses on both YAP1 and HPV to produce a more comprehensive approach to preventive screening, early detection and development of novel treatments.
"We think our work can be used one day for developing prevention methods for cervical cancer," he says, "And could improve treatment through finding new molecules and targeting new pathways."
However, despite the findings on HPV and the central role of YAP1, Dr. Wang emphasizes the continued importance for sexually active people to receive the HPV vaccine.
Dr. Wang's laboratory is combining their unique animal models with high throughput technologies to uncover molecular mechanisms by which hyperactivated YAP1 alone or in combination with HPV drives cervical carcinogenesis.
"It's a chicken and egg situation," says Dr. Wang. "Right now, we're not sure what comes first, so understanding that and translating it to patient care to save lives is our goal."
Learn more about the Vincent Center for Reproductive Biology
Learn more about the Center for Gynecologic Oncology