Notably, LncHIFCAR was greatly up-regulated in OSCC in our and others’ analyses of both western and Taiwanese populations. This enhanced LncHIFCAR signature has also further validated using miRNA/lncRNA expression profiles of patients with colon adenocarcinoma, glioblastoma breast and oral cancer from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. In addition, oral cancer patients with high LncHIFCAR expression levels had a significantly worse overall survival and recurrence-free survival rate than those with low LncHIFCAR expression. Most remarkably, multivariate analysis uncovered the clinical relevance of LncHIFCAR as an independent adverse prognostic predictor for the oral cancer progression. Given its significance in the HIF-1 signaling pathway, LncHIFCAR represents a novel and potential therapeutic target for the treatment of OSCC.

 

One of the unmet clinical needs in managing oral cancer patients is the identification of reliable biomarkers for early detection. Currently, most of the protein biomarkers identified for oral cancer are not clinically accessible, nor do they harbor sufficient sensitivity. Using lncRNA as a biomarker has, however, been shown to hold several advantages in light of its sensitivity, specificity, stability and easy accessibility. We uncovered a remarkable value of LncHIFCAR for oral cancer prognosis with the following evidence. First, a high LncHIFCAR level strongly associates with poor survival of oral cancer patients. Second, LncHIFCAR expression strongly correlates with poorly differentiated oral cancer, which is known to display early metastasis, and a high relapse rate and predicts poor outcomes in the patients. Finally, the multivariate analysis identified high LncHIFCAR as an independent risk factor for recurrence-free patient survival. Meanwhile, for decades, HIF-1 and its downstream effectors have long been recognized as potential targets for cancer drugs due to their profound impacts on cancer progression. However, the complexity of the HIF-1 signaling network has made the design of its inhibitors very challenging. Recently, RNA-based lncRNA targeting has been increasingly considered as a promising therapeutic strategy for cancer treatment. Because of the high expression level and the roles in HIF-1 activation in oral cancer, LncHIFCAR has great potential to be developed as a specific target for therapy. The roles of LncHIFCAR in HIF-1α co-activation and the translational relevance of LncHIFCAR described by our work not only provide new insights into HIF-1 activation but also reveal a potential utility of LncHIFCAR in prognosis and therapeutic strategies for oral cancer. We are also excited about the insights these findings have brought to the mechanism of acute ischemic stroke, because hypoxic tissues are often observed in this disease.

 

It has been shown that circulating noncoding RNAs could serve as potential disease biomarkers with high specificity, sensitivity, and noninvasive characteristics in clinical practice. This RNA-based liquid biopsy provides a minimally invasive alternative to profile molecular signatures for early-stage cancer detection, disease progression prediction and drug response monitoring to offer personalized therapeutic options. Given that LncHIFCAR is an RNA molecule crucial for hypoxia-mediated cancer progression and could be detected in body fluid in our test, our research group is currently implementing in-depth studies in validation of the clinical relevance of circulating LncHIFCAR, as well as genetic studies in patients with advanced oral cancer, hoping that these efforts could help identify novel biomarkers and preventive strategies beneficial to the patients.