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Rs4911154 of circ-ITCH aggravated tumor malignancy of thyroid nodules via the circ-ITCH/miR-22-3p/CBL axis.

ABSTRACT: Recent evidence revealed an inhibitory effect of circ-ITCH on the progression of papillary thyroid cancer via affecting the circ-ITCH/miR-22-3p/CBL axis. Rs4911154, an SNP located in circ-ITHC, was previously reported to be significantly associated with an increased risk of hepatocellular carcinoma. Ultrasound testing was used to evaluate the doubling time of thyroid nodules. 202 patients diagnosed with thyroid nodule disorders were divided into three groups according to their genotypes at rs4911154. We found that the A allele was correlated with a shortening doubling time of thyroid nodules. Moreover, the A allele contributed to reduced expression of circ-ITCH/CBL and increased expression of miR-22-3p. Besides, decreased tissue apoptosis was linked to the A allele. Luciferase assays indicated that miR-22-3p could effectively suppress the luciferase activities of CBL and circ-ITCH. Furthermore, manual up-regulation of miR-22-3p effectively suppressed the expression of CBL, while CBL siRNA apparently abolished circ-ITCH induced CBL upregulation, reduced proliferation and increased apoptosis of K1 and TPC-1 cells. A signaling pathway of circ-ITCH/miR-22-3p/CBL axis was established to explain the effect of SNP of circ-ITCH in thyroid tumor malignancy. Compared with the G allele, the A allele in rs4911154 contributed to the malignancy of thyroid nodules with decreased doubling time and down-regulated CBL expression.

SUBMITTER: Guo Y

PROVIDER: S-EPMC8445954 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Gene panels are routinely used to assess predisposition to hereditary cancers by simultaneously testing multiple susceptibility genes and/or variants. More recently, genetic panels have been implemented as part of solid tumor malignancy testing assessing somatic alterations. One example is targeted variant panels for thyroid nodules that are not conclusively malignant or benign upon fine-needle aspiration (FNA). We systematically reviewed published studies from 2009 to 2018 that contained genetic data from preoperative FNA specimens on cytologically indeterminate thyroid nodules (ITNs) that subsequently underwent surgical resection. Pooled prevalence estimates per gene and variant, along with their respective positive predictive values (PPVs) for malignancy, were calculated. Summary: Our systematic search identified 540 studies that were supplemented by 18 studies from bibliographies or personal files. Sixty-one studies met all inclusion criteria and included >4600 ITNs. Overall, 26% of nodules contained at least 1 variant or fusion. However, half of them did not include details on the specific gene, variant, and/or complete fusion pair reported for inclusion toward PPV calculations. The PPVs of genomic alterations reported at least 10 times were limited to BRAFV600E (98%, 95% confidence interval [CI 96-99%]), PAX8/PPARG (55% [CI 34-78%]), HRASQ61R (45% [CI 22-72%]), BRAFK601E (42% [CI 19-68%]), and NRASQ61R (38% [CI 23-55%]). Excluding BRAFV600E, the pooled PPV for all other specified variants and fusions was 47%. Multiple variants within the same nodule were identified in ∼1% of ITN and carried a cumulative PPV of 77%. Conclusions: The chance that a genomic alteration predicts malignancy depends on the individual variant or fusion detected. Only five alterations were reported at least 10 times; BRAFV600E had a PPV of 98%, while the remaining four had individual PPVs ranging from 38% to 55%. The small sample size of most variants and fusion pairs found among ITNs, however, limits confidence in their individual PPV point estimates. Better specific reporting of genomic alterations with cytological category, histological subtype, and cancer staging would facilitate better understanding of cancer prediction, and the independent contribution of the genomic profile to prognosis.

Project description:BackgroundThe aberrant expression of circular RNAs (circRNAs) plays vital roles in the advancement of human cancers, including gastric cancer (GC). In this study, the functions of circRNA ring finger protein 111 (circ-RNF111) in GC were investigated.MethodsQuantitative real-time polymerase chain reaction (qRT-PCR) assay was performed for the levels of circ-RNF111, microRNA-876-3p (miR-876-3p) and krueppel-like factor 12 (KLF12) mRNA. RNase R assay was conducted for the feature of circ-RNF111. Cell Counting Kit-8 (CCK-8) assay, colony formation assay, wound-healing assay, and transwell assay were applied for cell viability, colony formation, migration, and invasion, respectively. Flow cytometry analysis was used to analyze cell apoptosis and cell cycle process. The glycolysis level was examined using specific commercial kits. Western blot assay was carried out to measure the protein levels of hexokinase 2 (HK-2) and KLF12. Dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were employed to verify the combination between miR-876-3p and circ-RNF111 or KLF12. Murine xenograft model was constructed for the role of circ-RNF111 in vivo. Immunohistochemistry (IHC) was used for KLF12 level.ResultsCirc-RNF111 was higher expressed in GC tissues and cells than normal tissues and cells. Silencing of circ-RNF111 restrained cell viability, colony formation, migration, invasion, cell cycle process and glycolysis and induced apoptosis in GC cells in vitro. Circ-RNF111 positively regulated KLF12 expression via absorbing miR-876-3p. MiR-876-3p downregulation reversed the impacts of circ-RNF111 silencing on GC cell malignant phenotypes. MiR-876-3p overexpression repressed GC cell growth, metastasis and glycolysis, inhibited apoptosis and arrested cell cycle, while KLF12 elevation weakened the effects. Besides, circ-RNF111 knockdown inhibited tumor growth in vivo.ConclusionCirc-RNF111 knockdown relieved the development of GC by regulating miR-876-3p/KLF12 axis.

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Rs4911154 of circ-ITCH aggravated tumor malignancy of thyroid nodules via the circ-ITCH/miR-22-3p/CBL axis.

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