Abstract
Neuro-oncological ventral antigen 1 (NOVA1) is known as a neuron-specific pre-mRNA binding splicing factor. Previously, it was shown to be highly upregulated in T lymphocytes, as well as fibroblasts/stromal spindle cells, in tertiary lymphoid tissues formed by the benign immune-inflammatory process, while it was frequently downregulated in tumor cells and other cells within the tumor microenvironment. Here, we sought to identify the mechanisms of NOVA1 modulation in head and neck squamous cell carcinoma (HNSCC). NOVA1 was induced by inflammatory-immune signals within the tumor microenvironment and was suppressed by epigenetic dysregulation, such as that with miR-146. We found attenuated expression of NOVA1 to be associated with non-oropharynx sites such as oral cavity, hypopharynx, and larynx, human papilloma virus (HPV)-negative SCC defined by immunohistochemistry for p16INK4a expression, fewer tumor infiltrating lymphocytes, and poor patient outcomes. Moreover, changes were discovered in epithelial mesenchymal transition-associated markers according to NOVA1 status. This study provides some insights to the underlying mechanism of NOVA1 regulation and suggests that NOVA1 may serve as a prognostic biomarker and potential therapeutic target for HNSCC in the future.
Highlights
The development of chemoresistance and inability in elimination of cancer stem cells are among the key limitations of cancer chemotherapy
We show that EpCAM-aptamer-guided survivin RNAi effectively downregulated survivin both in colorectal cancer cells in vitro and in a mouse xenograft model for colorectal cancer
Our results indicate that survivin is one of the key players responsible for the innate chemoresistance of colorectal cancer stem cells
Summary
The development of chemoresistance and inability in elimination of cancer stem cells are among the key limitations of cancer chemotherapy. When combined with the conventional chemotherapeutic agents, the aptamer-guided survivin RNAi was able to enhance the sensitivity towards 5-FU or oxaliplatin in colorectal cancer stem cells, increase apoptosis, inhibit tumour growth and improve the overall survival of mice bearing xenograft colorectal cancer. Current approaches in treating cancer patients include surgical resection with chemotherapy or radiotherapy They are effective in eliminating the majority of the cancer cells, their inability to eliminate the cancer stem cell population remains a limitation for current regimen for cancer treatment[3,4,5,6,7]. We hypothesized that aptamer-mediated survivin RNAi enables 5-fluorouracil to eliminate colorectal cancer stem cells and improves the survival of the mice bearing xenograft tumour. We demonstrate that by silencing survivin expression in colorectal cancer stem cells using an aptamer-siRNA chimera, the innate chemoresistance to traditional chemotherapeutic agents in colorectal cancer stem cells was reversed, transforming an old anticancer drug into a cancer stem cell killer
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