Context: Exosomal miRNAs are considered potential non-invasive biomarkers for thyroid cancer. However, the global exosomal miRNAs profile for papillary thyroid cancer (PTC) has not been revealed. Objective: This study investigated the diagnostic value of plasma and serum exosomal miRNAs for PTC. Methods: Plasma and serum samples were collected from ten patients with benign thyroid nodules and 17 with PTC for small RNA sequencing. Plasma samples were collected from two independent cohorts, including 119 patients with PTC, 51 healthy people and 82 patients with benign thyroid nodules, for validation by quantitative reverse-transcription polymerase chain reaction (RT-qPCR). Results: Small RNA sequencing identified 41 putative exosomal miRNA biomarkers for PTC. Twelve miRNAs were selected for validation. miR-376a-3p, miR-4306, miR-4433a-5p, and miR-485-3p expression significantly increased in patients with PTC compared to that in healthy people and patients with benign thyroid nodules (P ˂ 0.05). Moreover, miR-485-3p and miR-4433a-5p presented larger areas under the curve (AUCs). The high expression of exosomal miR-485-3p correlated with tumor size greater than or equal to 1 cm, advanced clinical stage, extrathyroidal extension, BRAF mutation, and lymph node metastasis. Besides, miR-485-3p exhibited the highest AUCs in diagnosing PTC patients with high-risk factors. Conclusions: Plasma exosomal miR-485-3p and miR-4433a-5p might serve as biomarkers for PTC diagnosis. Plasma exosomal miR-485-3p could enable discrimination between high-risk and low-risk PTC.

Because of the lack of sensitivity to radiotherapy and chemotherapy, therapeutic options for renal clear cell carcinoma (KIRC) are scarce. Long noncoding RNAs (lncRNAs) play crucial roles in the progression of cancer. However, their functional roles and upstream mechanisms in KIRC remain largely unknown. Exploring the functions of potential essential lncRNAs may lead to the discovery of novel targets for the diagnosis and treatment of KIRC. Here, according to the integrated analysis of RNA sequencing and survival data in TCGA-KIRC datasets, cyclin-dependent kinase inhibitor 2B antisense lncRNA (CDKN2B-AS1) was discovered to be the most upregulated among the 14 lncRNAs that were significantly overexpressed in KIRC and related to shorter survival. Functionally, CDKN2B-AS1 depletion suppressed cell proliferation, migration, and invasion both in vitro and in vivo. Mechanistically, CDKN2B-AS1 exerted its oncogenic activity by recruiting the CREB-binding protein and SET and MYND domain-containing 3 epigenetic-modifying complex to the promoter region of Ndc80 kinetochore complex component (NUF2), where it epigenetically activated NUF2 transcription by augmenting local H3K27ac and H3K4me3 modifications. Moreover, we also showed that CDKN2B-AS1 interacted with and was stabilized by insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), an oncofetal protein showing increased levels in KIRC. The Kaplan–Meier method and receiver operating curve analysis revealed that patients whose IGF2BP3, CDKN2B-AS1 and NUF2 are all elevated showed the shortest survival time, and the combined panel (containing IGF2BP3, CDKN2B-AS1, and NUF2) possessed the highest accuracy in discriminating high-risk from low-risk KIRC patients. Thus, we conclude that the stabilization of CDKN2B-AS1 by IGF2BP3 drives the malignancy of KIRC through epigenetically activating NUF2 transcription and that the IGF2BP3/CDKN2B-AS1/NUF2 axis may be an ideal prognostic and diagnostic biomarker and therapeutic target for KIRC.

Objective: NFE2L3 is a member of the cap 'n' collar basic-region leucine zipper family. NFE2L3 has turned out to be associated with oxidative stress, but the relevance of NFE2L3 in hepatocellular carcinoma (HCC) has remained elusive. This study aimed to investigate the role of NFE2L3 in HCC and explore underlying mechanisms.

Long non-coding RNAs (lncRNAs) play important roles in tumorigenesis and cancer progression. The orphan nuclear receptor subfamily 4 group A member 1 (NR4A1) acts as an oncogene, and is involved in colorectal cancer (CRC) development. However, the mechanism through which lncRNA regulates NR4A1 expression remains unknown. We aimed to identify lncRNAs that regulate NR4A1 and assess their underlying mechanisms in CRC. We first identified an antisense lncRNA of NR4A1 that was up-regulated in CRC tissues and cells with rapid amplification of cDNA ends (RACE), and designated it as NR4A1AS. Spearman correlation analysis showed that NR4A1AS was positively correlated with NR4A1 mRNA levels in 37 CRC tissues. Mechanistically, NR4A1AS stabilized NR4A1 mRNA by forming RNA–RNA complexes via partial base-pairing and up-regulated NR4A1 expression in CRC cells. RNA immunoprecipitation (RIP) assays revealed that knockdown of NR4A1AS expression by siRNA enhanced up-frameshift 1 (UPF1) recruitment to NR4A1 mRNA, thereby decreasing NR4A1 mRNA stability. Moreover, depletion of NR4A1AS was found to mimic the effect of NR4A1 knockdown, specifically by suppressing cell proliferation, migration and invasion, and inducing apoptosis and cell cycle arrest. Accordingly, restoring NR4A1 expression ameliorated the effects of NR4A1AS knockdown on tumor growth and metastasis of CRC cells in vitro and in vivo. Thus, we conclude that NR4A1AS up-regulates NR4A1 expression by forming RNA–RNA complexes and blocking UPF1-mediated mRNA destabilization, and it functions in tumor growth and metastasis of CRC cells at least partly through regulating NR4A1, suggesting that NR4A1AS might be as a potential target for RNA-based anti-CRC drug studies.

Adipose tissue represents a candidate target for the treatment of metabolic illnesses, such as obesity. Brown adipose tissue (BAT), an important heat source within the body, promotes metabolic health through fat consumption. Therefore, the induction of white fat browning may improve lipid metabolism. Currently, the specific roles of circRNA in BAT and white adipose tissue (WAT) remain elusive. Herein, we conducted circRNA expression profiling of mouse BAT and WAT using RNA-seq. We identified a total of 12,183 circRNAs, including 165 upregulated and 79 downregulated circRNAs between BAT and WAT. Differentially expressed (DE) circRNAs were associated with the mitochondrion, mitochondrial part, mitochondrial inner membrane, mitochondrial envelope, therefore, these circRNAs may affect the thermogenesis and lipid metabolism of BAT. Moreover, DE circRNAs were enriched in browning- and thermogenesis-related pathways, including AMPK and HIF-1 signaling. In addition, a novel circRNA, circOgdh, was found to be highly expressed in BAT, formed by back-splicing of the third and fourth exons of the Ogdh gene, and exhibited higher stability than linear Ogdh. circOgdh was mainly distributed in the cytoplasm and could sponge miR-34a-5p, upregulating the expression of Atgl, a key lipolysis gene, which enhanced brown adipocyte lipolysis and suppressed lipid droplet accumulation. Our findings offer in-depth knowledge of the modulatory functions of circRNAs in BAT adipogenesis.

Nuclear factor erythroid 2‐like 3 (NFE2L3) is a member of the cap ‘n’ collar basic‐region leucine zipper (CNC‐bZIP) transcription factor family that plays a vital role in modulating oxidation–reduction steady‐state and proteolysis. Accumulating evidence suggests that NFE2L3 participates in cancer development; however, little is known about the mechanism by which NFE2L3 regulates hepatocellular carcinoma (HCC) cell growth. Here, we confirmed that NFE2L3 promotes HCC cell proliferation by acting as a transcription factor, which directly induces the expression of proteasome and interferon‐stimulated gene 15 (ISG15) to enhance the proteasome‐dependent degradation of ISGylated p53. Post‐translational ISGylation abated the stability of p53 and facilitated HCC cell growth. In summary, we uncovered the pivotal role of NFE2L3 in promoting HCC cell proliferation during proteostasis. This finding may provide a new target for the clinical treatment of HCC.