CircATRNL1 activates Smad4 signaling to inhibit angiogenesis and ovarian cancer metastasis via miR‐378

Wang, Juan; Li, Yan; Zhou, Jinhua; Shen, Fu‐Ming; Shi, Xiu; Chen, Youguo

doi:10.1002/1878-0261.12893

Cited by 25 publications

(21 citation statements)

References 49 publications

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“…None of the other three circRNAs (circFAT3, circATRNL1, and circITGA7) have been functionally linked to PC or described in expression studies in PC patient samples. However, both circITGA7 and circATRNL1 have been described as downregulated in other cancers, including colorectal cancer (CRC) (circITGA7, [ 34 , 35 ]) and ovarian cancer (circATRNL1, [ 36 ]), similar to our findings in PC. Moreover, circITGA7 and circATRNL1 have been reported to be involved in cell proliferation, invasion, and migration in CRC and ovarian cancer [ 34 , 36 ], supporting a potential functional role of these circRNA candidates in cancer development/progression.…”

Section: Discussionsupporting

confidence: 89%

The transcriptional landscape and biomarker potential of circular RNAs in prostate cancer

et al. 2022

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Background Circular RNAs (circRNAs) constitute a largely unexplored source for biomarker discovery in prostate cancer (PC). Here, we characterize the biomarker potential of circRNAs in PC, where the need for novel diagnostic and prognostic tools to facilitate more personalized management is pressing. Methods We profiled the transcriptomic landscape of circRNAs in PC by total RNA sequencing of 31 adjacent-normal and 143 tumor samples from localized (radical prostatectomy (RP)) and metastatic PC patients (cohort 1, training). Diagnostic and prognostic potential was evaluated in cohort 1, and 39 top circRNA candidates were selected for validation in two additional PC cohorts (cohort 2, n = 111; RP cohort 3, n = 191) by NanoString-based expression analysis. Biochemical recurrence (BCR)-free survival was assessed using Kaplan-Meier, univariate, and multivariate Cox regression analyses. The circRNA candidates were further detected in extracellular vesicle (EV)-enriched plasma samples from PC patients and controls (cohort 4, n = 54). Results Expression of circABCC4, circFAT3, circATRNL1, and circITGA7 was highly cancer-specific (area under the curve 0.71–0.86), while low circITGA7 expression was significantly (P < 0.05) associated with BCR in univariate analysis in two RP cohorts. Moreover, we successfully trained and validated a novel 5-circRNA prognostic signature (circKMD1A/circTULP4/circZNF532/circSUMF1/circMKLN1) significantly associated with BCR beyond routine clinicopathological variables (RP cohort 1: P = 0.02, hazard ratio = 2.1; RP cohort 3: P < 0.001, hazard ratio = 2.1). Lastly, we provide proof-of-principle for detection of candidate circRNAs in EV-enriched plasma samples from PC patients. Conclusions circRNAs hold great biomarker potential in PC and display both high cancer specificity and association to disease progression.

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Section: Discussionsupporting

confidence: 89%

The transcriptional landscape and biomarker potential of circular RNAs in prostate cancer

et al. 2022

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“…At present, seven studies have explored the roles of circATRNL1 ( Zhang et al, 2019a ; Wang et al, 2020a ; Chen et al, 2020 ; Wang et al, 2021a ; Wang et al, 2021b ; Zhang et al, 2021c ; Zheng et al, 2021 ), but three did not include has_circ_0020093 ( Chen et al, 2020 ; Wang et al, 2021b ; Zhang et al, 2021c ). In a study by Wang et al, circATRNL1 activated Smad4 signaling and suppressed angiogenesis and ovarian cancer metastasis by binding miR-378 ( Wang et al, 2021a ). Zhang et al found that circATRNL1 was downregulated in women with polycystic ovary syndrome ( Zhang et al, 2019a ).…”

Section: Discussionmentioning

confidence: 99%

CircATRNL1 and circZNF608 Inhibit Ovarian Cancer by Sequestering miR-152-5p and Encoding Protein

Lyu

Shen

et al. 2022

Front. Genet.

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Background: CircRNAs have been found to be involved in the pathogenesis of various diseases. We aimed to explore the roles of circRNAs in ovarian cancer.Methods: The expression levels of circRNAs in ovarian cancer and normal ovarian tissues were analyzed using RNA sequencing. Fluorescent in situ hybridization (FISH), proliferation assays and transwell assays were used to assess the effects of circRNAs on ovarian cancer.Results: CircATRNL1 and circZNF608 were downregulated in 20 ovarian cancer tissues compared to normal tissues. CircATRNL1 and circZNF608 are mainly located in the cytoplasm of ovarian cancer cells, and circATRNL1 is a highly conserved circRNA. The overexpression of circATRNL1 and circZNF608 inhibits the proliferation and invasion of ovarian cancer cells. We predicted miRNA–circRNA interactions for circZNF608 and circATRNL1 and obtained 63 interactions. However, a luciferase reporter assay showed that only miR-152-5p was sequestered by circZNF608. Bioinformatics analysis and experiments indicated that circATRNL1 contains an internal ribosome entry site and an open reading frame encoding a 131 aa protein.Conclusion: In conclusion, circATRNL1 and circZNF608 are two downregulated circRNAs in ovarian cancer and work as tumor suppressors. CircZNF608 may exert antitumor activity in ovarian cancer by binding miR-152-5p, and circATRNL1 may encode a 131 aa protein.

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“…For example, Izeradjene et al [ 57 ] revealed that the formation of mucinous cystic neoplasms is induced by synergistic effects of Kras-G12D and Smad4 mutations. The role of Smad4 in other human cancers, such as colorectal cancer (CRC)[ 58 ], gastric cancer[ 59 ], ovarian cancer[ 60 ] and head and neck squamous cell carcinoma (HNSCC)[ 61 ], is similar to that in pancreatic cancer. Downregulation of Smad4 is considered an early event of HNSCC, which is different from pancreatic cancer.…”

Section: Multiple Roles Of Smad4 In Tumorigenesismentioning

confidence: 99%

Multiple roles of mothers against decapentaplegic homolog 4 in tumorigenesis, stem cells, drug resistance, and cancer therapy

Dai¹,

Cao²,

Huang³

et al. 2022

WJSC

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The transforming growth factor (TGF)-β signaling pathway controls many cellular processes, including proliferation, differentiation, and apoptosis. Abnormalities in the TGF-β signaling pathway and its components are closely related to the occurrence of many human diseases, including cancer. Mothers against decapentaplegic homolog 4 (Smad4), also known as deleted in pancreatic cancer locus 4, is a typical tumor suppressor candidate gene locating at q21.1 of human chromosome 18 and the common mediator of the TGF-β/Smad and bone morphogenetic protein/Smad signaling pathways. It is believed that Smad4 inactivation correlates with the development of tumors and stem cell fate decisions. Smad4 also interacts with cytokines, miRNAs, and other signaling pathways, jointly regulating cell behavior. However, the regulatory function of Smad4 in tumorigenesis, stem cells, and drug resistance is currently controversial. In addition, Smad4 represents an attractive therapeutic target for cancer. Elucidating the specific role of Smad4 is important for understanding the mechanism of tumorigenesis and cancer treatment. Here, we review the identification and characterization of Smad4, the canonical TGF-β/Smad pathway, as well as the multiple roles of Smad4 in tumorigenesis, stem cells, and drug resistance. Furthermore, we provide novel insights into the prospects of Smad4-targeted cancer therapy and the challenges that it will face in the future.

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CircATRNL1 activates Smad4 signaling to inhibit angiogenesis and ovarian cancer metastasis via miR‐378

Cited by 25 publications

References 49 publications

The transcriptional landscape and biomarker potential of circular RNAs in prostate cancer

The transcriptional landscape and biomarker potential of circular RNAs in prostate cancer

CircATRNL1 and circZNF608 Inhibit Ovarian Cancer by Sequestering miR-152-5p and Encoding Protein

Multiple roles of mothers against decapentaplegic homolog 4 in tumorigenesis, stem cells, drug resistance, and cancer therapy

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