RESUMO
Elevated CUB-domain containing protein 1 (CDCP1) is predictive of colorectal cancer (CRC) recurrence and poor patient survival. While CDCP1 expression identifies stem cell populations that mediate lung metastasis, mechanisms underlying the role of this cell surface receptor in CRC have not been defined. We sought to identify CDCP1 regulated processes in CRC using stem cell populations, enriched from primary cells and cell lines, in extensive in vitro and in vivo assays. These experiments, demonstrating that CDCP1 is functionally important in CRC tumor initiation, growth and metastasis, identified CDCP1 as a positive regulator of Wnt signaling. Detailed cell fractionation, immunoprecipitation, microscopy, and immunohistochemical analyses demonstrated that CDCP1 promotes translocation of the key regulators of Wnt signaling, ß-catenin, and E-cadherin, to the nucleus. Of functional importance, disruption of CDCP1 reduces nuclear localized, chromatin-associated ß-catenin and nuclear localized E-cadherin, increases sequestration of these proteins in cell membranes, disrupts regulation of CRC promoting genes, and reduces CRC tumor burden. Thus, disruption of CDCP1 perturbs pro-cancerous Wnt signaling including nuclear localization of ß-catenin and E-cadherin.
Assuntos
Antígenos de Neoplasias/genética , Caderinas/genética , Moléculas de Adesão Celular/genética , Neoplasias Colorretais/genética , beta Catenina/genética , Transporte Ativo do Núcleo Celular/genética , Carcinogênese/genética , Proliferação de Células/genética , Neoplasias Colorretais/patologia , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica/genética , Células HCT116 , Humanos , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Via de Sinalização Wnt/genéticaRESUMO
BACKGROUND: Recent evidence has challenged the practice of tonsillectomy in children with sleep-disordered breathing. Tonsillotomy (subtotal/partial/intracapsular tonsillectomy) has been proposed as an alternative with equivalent effectiveness and decreased post-operative morbidity, thus improving cost-effectiveness. OBJECTIVE: To systematically review the literature comparing clinical efficacy, post-operative morbidity, and cost-effectiveness of tonsillotomy and tonsillectomy in paediatric (<16yo) patients with sleep-disordered breathing. DATA SOURCES: A systematic search of MEDLINE, EMBASE, and CENTRAL (1984-July 2014) was conducted. Papers in English directly comparing post-operative outcomes in tonsillectomy and tonsillotomy in children undergoing surgery for sleep-disordered breathing were included. REVIEW METHODS: Two authors independently assessed abstracts for relevance, with disagreements resolved by a third author. Selected studies were independently assessed regarding inclusion and exclusion criteria. RESULTS: Thirty-two studies satisfied inclusion and exclusion criteria (19 randomised, 13 non-randomised). Patient satisfaction, quality-of-life, and polysomnographic improvement post-surgery did not vary between tonsillotomy and tonsillectomy. Tonsillotomy reduced the odds of a secondary haemorrhage by 79% (OR 0.21, 95% CI 0.17-0.27, p < 0.01), decreased post-operative pain and reduced return to normal oral intake by 2.8 days (95% CI 1.08-4.52, p < 0.01). The odds of readmission were decreased by 62% (OR 0.38, 95% CI 0.23-0.60, p < 0.01). Tonsillotomy had a slightly higher rate of symptom recurrence (4.51%) than tonsillectomy (2.55%), the long-term impact of which was unclear. CONCLUSION: Current evidence supports tonsillotomy in children with obstructive surgical indications. It is likely to reduce post-operative haemorrhage, pain, and facilitate a faster return to normal diet and activity. Healthcare burden is decreased due to fewer post-operative complications and reduced need for medical re-contact. More research is necessary to assess the risk of recurrence, and further classification of secondary haemorrhage severity is required to fully clarify the clinical benefit of tonsillotomy.
