September 25, 2019
Study identifies novel therapeutic approach for head and neck squamous cell carcinoma
BY Jill Russell, Ph.D.
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer globally. Even with multimodality treatment, including surgery, radiation, and chemotherapy, the 5-year survival rate remains at 60%.
Although epidermal growth factor receptor (EGFR) is frequently overexpressed in head and neck cancers, EGFR inhibitors have not been as effective as anticipated in the clinic, suggesting that other cellular pathways are involved.
“Small molecule inhibitors have not been as effective as expected in head and neck squamous cell carcinoma, so we wanted to try a different approach. We’re just starting to understand the biology of microRNA and its therapeutic potential,” says Stephen Lai, M.D., Ph.D., professor of Head and Neck Surgery at The University of Texas MD Anderson Cancer Center. MicroRNAs are small non-coding RNAs that regulate gene expression.
MicroRNA miR-27a targets EGFR
Lai and his research team, including Nikhi Chari, Ph.D., discovered that miR-27a and its complementary strand miR-27a* target EGFR in HNSCC cells. They found that mir-27a* expression, previously thought to be nonfunctional, also decreases cell viability in HNSCC and also pancreatic, prostate, and endometrial carcinoma cell lines. In their most recent study, published in the Journal of the National Cancer Institute, the research team explores the regulatory mechanisms of miR-27a* in head and neck cancers.
Through quantitative real-time polymerase chain reaction analysis of patient tumor samples, the researchers found that miR-27a* expression was lower in tumor samples than in matched normal tissues. They also found higher miR-27a* levels in human papillomavirus (HPV)-positive tumors, which have a better prognosis than do HPV-negative tumors. Low levels of miR-27a* in patients with HPV-positive cancer were associated with high-grade, poorly differentiated tumors and worse survival.
The researchers conducted a series of knockdown experiments and identified the role of miR-27a* in a regulatory feedback loop where: ΔNp63⍺ activates miR-27a* transcription, and increased levels of miR-27a* decrease ΔNp63⍺ protein.
miR-27a* also targets nucleoporin 62 (NUP62), which regulates ΔNp63⍺ transport into the cell nucleus and may play an independent role as an oncogene in squamous cell carcinoma.
However, mutant TP53, which occurs in 70% of head and neck tumors, disrupts this balance, leading to decreased miR-27a* expression and increased ΔNp63⍺ and NUP62 levels. “ΔNp63⍺ is crucial to HNSCC survival because ΔNp63⍺ represses the transcription involved in apoptosis,” Lai says.
New strategy for treating cancer
In addition to targeting EGFR and ΔNp63⍺, miR-27a* also hits AKT1 and mTOR, which are key oncogenes in the same signaling pathway, the most activated network in both HPV-positive and HPV-negative HNSCC. ΔNp63⍺ upregulates AKT1, leading to tumor resistance to cisplatin, which is the main treatment option for advanced HNSCC. The microRNA’s ability to target multiple components of this oncogenic pathway that is critical for HNSCC survival makes it a promising option for throat cancer treatment.
“Part of our future research will focus on finding a means to deliver miR-27a* to cancer cells,” Lai says.
This study helps open up a new strategy for treating cancer in general, especially since miR-27a* has been shown to act as a tumor suppressor in cell lines from other types of cancer. The US Food and Drug Administration approved the first microRNA-based therapy only last year. “In this age of targeted therapy,” Lai says, “microRNA-based treatments are just beginning.”