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- Chen, Baoqing, et al.
(författare)
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The Long Noncoding RNA CCAT2 Induces Chromosomal Instability Through BOP1-AURKB Signaling
- 2020
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Ingår i: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 159:6, s. 2146-2162
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Tidskriftsartikel (refereegranskat)abstract
- Background & AimsChromosomal instability (CIN) is a carcinogenesis event that promotes metastasis and resistance to therapy by unclear mechanisms. Expression of the colon cancer–associated transcript 2 gene (CCAT2), which encodes a long noncoding RNA (lncRNA), associates with CIN, but little is known about how CCAT2 lncRNA regulates this cancer enabling characteristic.MethodsWe performed cytogenetic analysis of colorectal cancer (CRC) cell lines (HCT116, KM12C/SM, and HT29) overexpressing CCAT2 and colon organoids from C57BL/6N mice with the CCAT2 transgene and without (controls). CRC cells were also analyzed by immunofluorescence microscopy, γ-H2AX, and senescence assays. CCAT2 transgene and control mice were given azoxymethane and dextran sulfate sodium to induce colon tumors. We performed gene expression array and mass spectrometry to detect downstream targets of CCAT2 lncRNA. We characterized interactions between CCAT2 with downstream proteins using MS2 pull-down, RNA immunoprecipitation, and selective 2′-hydroxyl acylation analyzed by primer extension analyses. Downstream proteins were overexpressed in CRC cells and analyzed for CIN. Gene expression levels were measured in CRC and non-tumor tissues from 5 cohorts, comprising more than 900 patients.ResultsHigh expression of CCAT2 induced CIN in CRC cell lines and increased resistance to 5-fluorouracil and oxaliplatin. Mice that expressed the CCAT2 transgene developed chromosome abnormalities, and colon organoids derived from crypt cells of these mice had a higher percentage of chromosome abnormalities compared with organoids from control mice. The transgenic mice given azoxymethane and dextran sulfate sodium developed more and larger colon polyps than control mice given these agents. Microarray analysis and mass spectrometry indicated that expression of CCAT2 increased expression of genes involved in ribosome biogenesis and protein synthesis. CCAT2 lncRNA interacted directly with and stabilized BOP1 ribosomal biogenesis factor (BOP1). CCAT2 also increased expression of MYC, which activated expression of BOP1. Overexpression of BOP1 in CRC cell lines resulted in chromosomal missegregation errors, and increased colony formation, and invasiveness, whereas BOP1 knockdown reduced viability. BOP1 promoted CIN by increasing the active form of aurora kinase B, which regulates chromosomal segregation. BOP1 was overexpressed in polyp tissues from CCAT2 transgenic mice compared with healthy tissue. CCAT2 lncRNA and BOP1 mRNA or protein were all increased in microsatellite stable tumors (characterized by CIN), but not in tumors with microsatellite instability compared with nontumor tissues. Increased levels of CCAT2 lncRNA and BOP1 mRNA correlated with each other and with shorter survival times of patients.ConclusionsWe found that overexpression of CCAT2 in colon cells promotes CIN and carcinogenesis by stabilizing and inducing expression of BOP1 an activator of aurora kinase B. Strategies to target this pathway might be developed for treatment of patients with microsatellite stable colorectal tumors.
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| 2. |
- Krishnan, Nellai, et al.
(författare)
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Role of Magnetic Compression Anastomosis in Long-Gap Esophageal Atresia : A Systematic Review
- 2023
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Ingår i: Journal of Laparoendoscopic and Advanced Surgical Techniques. - : Mary Ann Liebert. - 1092-6429 .- 1557-9034. ; 33:12, s. 1223-1230
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Forskningsöversikt (refereegranskat)abstract
- Background: Magnetic compression anastomosis (MCA) is an alternative technique for patients with long-gap esophageal atresia (EA). It allows for preservation of the native esophagus. We aimed to systematically summarize the current literature on MCA in EA.Methods: Studies where neonates with EA were treated with MCA devices were included, while studies on esophageal stenosis were excluded. All clinical studies, including comparative studies, case series, and case reports, were eligible for inclusion. Methodological quality assessment was performed using a validated tool.Results: Twelve studies with a total of 42 patients were included in this review. There was a wide variation among these studies with regard to the time of initiation of MCA (1 day to 7 months), procedure time (13–320 minutes), and magnet characteristics (strength, size, and shape of the magnets used). The time to achieve anastomosis ranged from 1 to 12 days. Stricture at the anastomotic site was reported in almost all the patients, which required multiple endoscopic dilatations (median no. of dilatations/patient = 9.8). Stent placement for refractory stricture was required in 9 (21%) patients, and surgery for stricture was required in 6 (14%) patients. Long-term outcomes included esophageal dysmotility (n = 3) and recurrent pulmonary infections (n = 3) were reported in only four studies.Conclusion: As per the findings of this review, neonates with long-gap EA undergoing MCA would invariably require multiple sittings of endoscopic dilatations (median no. of dilatations/patient = 9.8). Also, there is a wide variation among the included studies in terms of the procedure of MCA. Future studies with a standardized procedure for achieving MCA are needed to determine additional outcomes in this fragile patient population.
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