Abstract
A growing body of evidence has shown that circular RNA (circRNA) is a promising exosomal cancer biomarker candidate. However, global circRNA alterations in cancer and the underlying mechanism, essential for identification of ideal circRNA cancer biomarkers, remain under investigation. We comparatively analyzed the circRNA landscape in pan-cancer and pan-normal tissues. Using co-expression and LASSO regularization analyses, as well as a support vector machine, we analyzed 265 pan-cancer and 319 pan-normal tissues in order to identify the circRNAs with the highest ability to distinguish between pan-cancer and pan-normal tissues. We further studied their expression in plasma exosomes from patients with cancer and their relation with cancer mutations and tumor microenvironment landscape. We discovered that circRNA expression was globally reduced in pan-cancer tissues and plasma exosomes from cancer patients than in pan-normal tissues and plasma exosomes from healthy controls. We identified dynein axonemal heavy chain 14 (DNAH14), the top back-spliced gene exclusive to pan-cancer tissues, as the host gene of three pan-cancer tissue-enriched circRNAs. Among these three circRNAs, chr1_224952669_224968874_+ was significantly elevated in plasma exosomes from hepatocellular carcinoma and colorectal cancer patients. It was also related to the cancer mutation chr1:224952669: G>A, a splice acceptor variant, and was increasingly transcription-driven in cancer tissues. Moreover, pan-cancer tissue-enriched and pan-normal tissue-enriched circRNAs were associated with distinct tumor microenvironment patterns. Our machine learning-based analysis provides insights into the aberrant landscape and biogenesis of circRNAs in cancer and highlights cancer mutation-related and DNAH14-derived circRNA, chr1_224952669_224968874_+, as a potential cancer biomarker.
Highlights
Circular RNA is a covalently closed circular and singlestranded non-coding RNA universally generated by cancer and normal cells and has been detected in plasma exosomes derived from these cells [1]
CircRNAs are gaining increasing attention as promising cancer biomarkers that can be detected by liquid biopsies and are associated with many cancer types, such as gastric cancer, colorectal cancer (CRC), hepatocellular carcinoma (HCC) and pancreatic adenocarcinoma (PAAD) [2], etc
We examined the expression of pan-cancer tissue-enriched and pan-normal tissue-enriched circRNAs in plasma exosomes from patients with cancer (HCC, CRC, PAAD) and healthy controls
Summary
Circular RNA (circRNA) is a covalently closed circular and singlestranded non-coding RNA universally generated by cancer and normal cells and has been detected in plasma exosomes derived from these cells [1]. Circ-KIAA1244 was downregulated in gastric tissues and plasma samples in patients with gastric cancer, and this decrease was negatively correlated with the TNM stage, lymphatic metastasis, and overall survival of patients [3]. Zhang et al showed that the elevation of circUHRF1 in HCC tissues and plasma exosomes was correlated with poor prognosis and resistance to anti-PD1 immunotherapy [5]. The Cancer-Specific CircRNA Database (CSCD) contains circRNA classifications that are “cancer-specific”, “normalspecific” or “common” based on the analysis of hundreds of pan-cancer and pan-normal tissue samples [7]. The circAtlas database contains circRNA profiles from thousands of samples across 19 different pan-normal tissues, showing that circRNAs can be cell-type specific and species-conserved [9, 10]. The exoRbase database is a collection of exosomal circRNA, lncRNA, and mRNA profiles from patients with cancer and healthy controls [11]
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