ABSTRACT
Ovarian cancer is a major gynecological cancer that has poor prognosis associated mainly to its late diagnosis. Cisplatin is an FDA approved ovarian cancer therapy and even though the therapy is initially promising, the patients mostly progress to resistance against cisplatin. The underlying mechanisms are complex and not very clearly understood. Using two different paired cell lines representing cisplatin-sensitive and the cisplatin-resistant ovarian cancer cells, the ES2 and the A2780 parental and cisplatin-resistant cells, we show an elevated proto-oncogene c-Myb in resistant cells. We further show down-regulated lncRNA NKILA in resistant cells with its de-repression in resistant cells when c-Myb is silenced. NKILA negatively correlates with cancer cell and invasion but has no effect on cellular proliferation or cell cycle. C-Myb activates NF-κB signaling which is inhibited by NKILA. The cisplatin resistant cells are also marked by upregulated stem cell markers, particularly LIN28A and OCT4, and downregulated LIN28A-targeted let-7 family miRNAs. Whereas LIN28A and downregulated let-7s individually de-repress c-Myb-mediated cisplatin resistance, the ectopic expression of let-7s attenuates LIN28A effects, thus underlying a c-Myb-NKILA-LIN28A-let-7 axis in cisplatin resistance of ovarian cancer cells that needs to be further explored for therapeutic intervention.
Subject(s)
Cisplatin , Down-Regulation , Drug Resistance, Neoplasm , MicroRNAs , Ovarian Neoplasms , Proto-Oncogene Mas , Proto-Oncogene Proteins c-myb , RNA, Long Noncoding , RNA-Binding Proteins , Humans , Cisplatin/pharmacology , Cisplatin/therapeutic use , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Female , Ovarian Neoplasms/genetics , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/pathology , Drug Resistance, Neoplasm/genetics , MicroRNAs/genetics , MicroRNAs/metabolism , Cell Line, Tumor , Proto-Oncogene Proteins c-myb/metabolism , Proto-Oncogene Proteins c-myb/genetics , RNA-Binding Proteins/metabolism , RNA-Binding Proteins/genetics , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Signal Transduction/drug effects , Cell Proliferation/drug effectsABSTRACT
RATIONALE: Clinically mild encephalitis/encephalopathy with a reversible splenial lesion of the corpus callosum (MERS) is a recently identified clinically and radiologically distinct syndrome. Clinical symptoms and lesions on the magnetic resonance imaging (MRI) often disappear in 1 week or a few weeks. However, MERS manifesting as a severe clinical course with significant sequela has not yet been reported. PATIENT CONCERNS: A 42-year-old male presented with a 3-day history of headache, fever, and irrational speech. Physical examination showed a body temperature of 39.5°C, dysarthria, dyscalculia, recent memory disturbance, and otherwise normal vital signs. The patient developed status epilepticus and progressive consciousness disturbance. MRI showed abnormal patchy signals in the splenium of the corpus callosum. DIAGNOSIS: The clinical feature and the characteristic of MRI are mostly consistent with MERS. At the same time, we made a differential diagnosis by testing the NMDARAb, AMPA1Ab, AMPA2Ab, LG1Ab, CASPR2Ab, GABABRAb in CSF and serum. INTERVENTIONS: The subject was treated with ganciclovir, antiepileptic, and antipyretic therapy. OUTCOMES: The subject was living a virtually normal life with persistent mild memory disturbance. MRI showed that the abnormal signals in the splenium of the corpus callosum had disappeared, but hyperintensity on T2-weighted and FLAIR imaging was noted in the centrum semiovale. LESSONS: MERS is a rare clinicoradiological syndrome, which can manifest as severe symptoms as well. Early diagnosis and treatment should be emphasized, and the diagnostic value of MRI is highlighted. Clinicians should be alert to the potential sequela.
