Cancer is one of the most frequently diagnosed malignant diseases worldwide, posing a serious, long-term threat to patients’ health and life. Systemic chemotherapy remains the first-line therapeutic approach for recurrent or metastatic cancer patients after surgery, with the potential to effectively extend patient survival. However, the development of drug resistance seriously limits the clinical efficiency of chemotherapy and ultimately results in treatment failure and patient death. A large number of studies have shown that non-coding RNAs (ncRNAs), particularly microRNAs, long non-coding RNAs, and circular RNAs, are widely involved in the regulation of cancer drug resistance. Their dysregulation contributes to the development of cancer drug resistance by modulating the expression of specific target genes involved in cellular apoptosis, autophagy, drug efflux, epithelial-to-mesenchymal transition (EMT), and cancer stem cells (CSCs). Moreover, some ncRNAs also possess great potential as efficient, specific biomarkers in diagnosis and prognosis as well as therapeutic targets in cancer patients. In this review, we summarize the recent findings on the emerging role and underlying mechanisms of ncRNAs involved in cancer drug resistance and focus on their clinical applications as biomarkers and therapeutic targets in cancer treatment. This information will be of great benefit to early diagnosis and prognostic assessments of cancer as well as the development of ncRNA-based therapeutic strategies for cancer patients.

https://www.frontiersin.org/articles/10.3389/fonc.2022.951864/pdf

Non-coding RNA in cancer drug resistance: Underlying mechanisms and clinical applications

Circular RNAs (circRNAs) are non-coding single-stranded covalently closed circular RNA, mainly produced by reverse splicing of exons of precursor mRNAs (pre-mRNAs). The characteristics of high abundance, strong specificity, and good stability of circRNAs have been discovered. A large number of studies have reported its various functions and mechanisms in biological events, such as the occurrence and development of cancer. In this review, we focus on the classification, characterization, biogenesis, functions of circRNAs, and the latest advances in cancer research. The development of circRNAs as biomarkers in cancer diagnosis and treatment also provides new ideas for studying circRNAs research.

/pdf/circular-rna-and-its-roles-in-the-occurrence-development-1sdbk5pw.pdf

Circular RNA and Its Roles in the Occurrence, Development, Diagnosis of Cancer

Circular RNAs (circRNAs) can be encapsulated into exosomes to participate in intercellular communication, affecting the malignant progression of a variety of tumors. Dysfunction of CD8 + T cells is the main factor in immune escape from hepatocellular carcinoma (HCC). Nevertheless, the effect of exosome-derived circRNAs on CD8 + T-cell dysfunction needs further exploration.The effect of circCCAR1 on the tumorigenesis and metastasis of HCC was assessed by in vitro and in vivo functional experiments. The function of circCCAR1 in CD8 + T-cell dysfunction was measured by enzyme-linked immunosorbent assay (ELISA), western blotting and flow cytometry. Chromatin immunoprecipitation, biotinylated RNA pull-down, RNA immunoprecipitation, and MS2 pull-down assays were used to the exploration of mechanism. A mouse model with reconstituted human immune system components (huNSG mice) was constructed to explore the role of exosomal circCCAR1 in the resistance to anti-PD1 therapy in HCC.Increased circCCAR1 levels existed in tumor tissues and exosomes in the plasma of HCC patients, in the culture supernatant and HCC cells. CircCCAR1 accelerated the growth and metastasis of HCC in vitro and in vivo. E1A binding protein p300 (EP300) and eukaryotic translation initiation factor 4A3 (EIF4A3) promoted the biogenesis of circCCAR1, and Wilms tumor 1-associated protein (WTAP)-mediated m6A modification enhanced circCCAR1 stability by binding insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3). CircCCAR1 acted as a sponge for miR-127-5p to upregulate its target WTAP and a feedback loop comprising circCCAR1/miR-127-5p/WTAP axis was formed. CircCCAR1 is secreted by HCC cells in a heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1)-dependent manner. Exosomal circCCAR1 was taken in by CD8 + T cells and caused dysfunction of CD8 + T cells by stabilizing the PD-1 protein. CircCCAR1 promoted resistance to anti-PD1 immunotherapy. Furthermore, increased cell division cycle and apoptosis regulator 1 (CCAR1) induced by EP300 promoted the binding of CCAR1 and β-catenin protein, which further enhanced the transcription of PD-L1.The circCCAR1/miR-127-5p/WTAP feedback loop enhances the growth and metastasis of HCC. Exosomal circCCAR1 released by HCC cells contributes to immunosuppression by facilitating CD8 + T-cell dysfunction in HCC. CircCCAR1 induces resistance to anti-PD1 immunotherapy, providing a potential therapeutic strategy for HCC patients. 

/pdf/exosome-derived-circccar1-promotes-cd8-t-cell-dysfunction-2m6td703.pdf

Exosome-derived circCCAR1 promotes CD8 + T-cell dysfunction and anti-PD1 resistance in hepatocellular carcinoma

Objective Evidence increasingly shows that circular RNAs (circRNAs) are closely associated with tumorigenesis and cancer progression. However, the roles of circRNAs and the underlying mechanism behind these circRNAs in gastric cancer (GC) remain to be elucidated. This study is aimed at conferring a better understanding of GC pathogenesis with a specific focus on circRNA-based ceRNA action. Methods circRNA expression profiles were downloaded from two Gene Expression Omnibus (GEO) microarray datasets, GSE152309 and GSE121445. Expression profiles of miRNAs and mRNAs were collected from The Cancer Genome Atlas (TCGA) database. The ceRNA network was constructed based on circRNA-miRNA pairs and miRNA-mRNA pairs. Functional and pathway enrichment analyses were performed to evaluate functional pathways of differentially expressed mRNAs (DEmRNAs). The PPI network was constructed by mapping DEmRNAs into the STRING database to identify hub genes, and then the DEcircRNA-DEmiRNA-hub gene subnetwork was constructed. The expression levels of candidate differentially expressed circRNAs (DEcircRNAs) in cancerous and matched noncancerous gastric tissues surgically resected from 52 GC patients were determined by the RT-qPCR analysis. Results Differential expression analysis with Venn diagram analysis showed 11 overlapped DEcircRNAs (7 upregulated circRNAs and 4 downregulated ones) between cancerous tissues and noncancerous gastric tissues. The DEcircRNA-DEmiRNA-DEmRNA network was constructed, consisting of 2 DEcircRNAs, 7 DEmiRNAs, and 104 DEmRNAs. GO and KEGG pathway analyses revealed that 104 DEmRNAs might be associated with GC development and progression. The PPI network was constructed, yielding 16 hub genes, TFDP1, KRAS, LMNB1, MET, MYBL2, CDC25A, E2F5, HMGA1, HMGA2, CBFB, CBX3, CDC7, IGF2BP3, KIF11, PDGFB, and SMC1A, which were all upregulated in GC tissues compared with adjacent tumor-free gastric tissues. Based on the above hub genes in GC, the DEcircRNA-DEmiRNA-hub gene subnetwork was reconstructed based on hsa_circ_0000384 and hsa_circ_0000043, including 22 pairs of the upcircRNA-downmiRNA-upmRNA network. The expression levels of hsa_circ_0000384 and hsa_circ_0000043 were remarkably higher in GC tissues than those in matched adjacent tumor-free gastric tissues (p < 0.001), concurring with the bioinformatics results. Conclusion Our study offers a better understanding of circRNA-related ceRNA regulatory mechanism in the pathogenesis of GC, highlighting two ceRNA networks based on hsa_circ_0000384 and hsa_circ_0000043.

/pdf/identification-of-novel-circrna-based-cerna-network-involved-3ukvoi4h.pdf

Identification of Novel circRNA-Based ceRNA Network Involved in the Pathogenesis of Gastric Cancer

Circular RNA circPBX3 promotes cisplatin resistance of ovarian cancer cells via interacting with IGF2BP2 to stabilize ATP7A mRNA expression

circMRPS35 promotes malignant progression and cisplatin resistance in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC), a common malignant tumor, is one of the main causes of cancer-related deaths worldwide. Circular RNAs (circRNAs), a novel class of non-coding RNA, have been reported to be involved in the etiology of various malignancy. However, the functions of circRNAs in HCC remain unclear. In this study, through mining the RNA sequencing databases from GEO datasets and subsequent experimental verification, we identified that hsa_circ_0000384 (circMRPS35) was highly expressed in HCC. Knockdown of circMRPS35 suppressed the proliferation, migration, invasion, clone formation and cell cycle of HCC cell lines both in vitro and in a xenograft mouse model. Mechanically, circMRPS35 sponged microRNA-148a-3p (miR-148a), which in turn regulated STX3-PTEN axis. Surprisingly, we detected a peptide encoded by circMRPS35 (circMRPS35-168aa), which was significantly induced by chemotherapeutic drugs and promoted cisplatin resistance in HCC cells. These results demonstrated that circMRPS35 might be a novel factor in HCC progress, and has a great potential as a new diagnosis and therapeutic target for treatment of HCC.

/pdf/circmrps35-promotes-malignant-progression-and-cisplatin-5c1wcfrta3.pdf

Fan Yin

Papers

circMRPS35 promotes malignant progression and cisplatin resistance in hepatocellular carcinoma.

circMRPS35 promotes malignant progression and cisplatin resistance in hepatocellular cancer