ABSTRACT
Alternative splicing is the key to human gene expression regulation and plays a decisive role in enlarging the diversity of functional proteins. Alternative splicing is an important biomarker in tumor progression, which is closely related to the development of tumors. Tumor cells tend to produce alternative spliceosome that are conducive to their progression. Therefore, targeting regulation of tumor-specific alternative spliceosomes is a potential strategy for tumor therapy. Herein, we provide a brief review of the complex relationship between alternative splicing and tumors. Alternative splicing works by removing non-coding sequences of pre-mRNA and assembling protein-coding fragments in different combinations, ultimately producing proteins with different or even opposite functions. Alternative splicing events can promote the transformation of tumor cells through apoptosis, invasion, metastasis, angiogenesis, and metabolism; they can also influence the effectiveness of cancer immunotherapy by affecting genes that play a key role in the immune pathway. We proposed that direct or indirect targeting of alternative splicing factors and oligonucleotide-based therapies are the main strategies to reverse tumor alternative splicing events. These findings will help us to better understand tumor-related alternative splicing and to develop new strategies for tumor treatment.
ABSTRACT
The carbamoyl phosphate synthase 1 (CPS1) enzyme is involved in the first phase of the urea cycle, providing a prerequisite molecule for pyrimidine synthesis, as well as promoting tumor cell proliferation and growth. Studies have found that CPS1 is highly expressed in a variety of tumors, including colorectal cancer, lung cancer, etc. and its overexpression is related to the poor prognosis of tumors. Thus, small molecules targeted to inhibit the function of CPS1 in tumors may provide therapeutic benefits for cancer patients who overexpress CPS1. In this study, the function of CPS1 was investigated in vitro, and we found that overexpression of CPS1 can enhance the migration ability of colorectal cancer cells HCT15. Here, based upon the existing crystal structure, combined with high-throughput virtual screening, we obtained 8 candidate small molecule compounds. In vitro activity evaluation, we found that compound 3 has good anti-HCT15, HCT116 cell proliferation activity (HCT15, IC50, 7.69 ± 1.10 μmol‧L-1, HCT116, IC50, 13.53 ± 0.46 μmol‧L-1). Subsequently, molecular docking and molecular dynamics (MD) simulation analysis showed that, compound 3 could target and inhibit the activity of CPS1. In vitro studies showed that compound 3 could inhibit the migration of HCT15 cells, as well as induced cell cycle arrest and apoptosis. Taken together, this study found that compound 3 is a potential small molecule inhibitor that targets CPS1, which provides the experimental basis and theoretical basis for the development of targeted intervention small molecule therapeutic drugs. Based upon the chemical structure of compound 3, we will shed new light on further optimizing its activity and therapeutic potential, which may provide a therapeutic benefit to the patients with CPS1-related tumors.
ABSTRACT
Background: To investigate the feasibility and safety of computed tomography-magnetic resonance imaging (CT-MRI) fusion-guided iodine-125 seed implantation for a single malignant brain tumor. Methods: From November 2015 to October 2016, 12 patients with a single malignant brain tumor were treated with permanent iodine-125 seeds implantation. CT-MRI fusion images were used to make the preoperative treatment plan, intraoperative dose optimization, postoperative verification, and tumor response follow-up. The dosimetry parameters of CT-MRI image fusion plans were compared between preprocedures and postprocedures, including plan target volume, V100 (the percentage of the target volume covered by the prescription dose [PD]), D90 (the dose that covers 90% of the target volume), and V200 (the percentage volume of the brain tumor receiving 200% of the PD). Adverse events were graded by the Common Terminology Criteria for Adverse Events. Clinical and radiological follow-ups were performed at a 3-month interval. Results: All the interstitial implantations were completed successfully under the guidance of CT-MRI image fusion. The dosimetry parameters of CT-MRI image fusion postplans did not differ significantly from those of preplans (P > 0.05). No higher than Grade 2 adverse events were observed during the follow-up. Tumor control was achieved in 10 of 12 patients (83.33%). The median overall survival time was 15.05 ± 3.35 months (95% confidence interval 12.99–17.26). Conclusions: CT-MRI image fusion is feasible for the design, optimization, and verification of treatment planning. CT-MRI fusion-based brachytherapy may improve dosimetry of brain tumor while sparing the normal structures, potentially impacting disease control, treatment-related toxicity, and long-term survival