A computational approach for structural and functional analyses of disease-associated mutations in the human CYLD gene.

Tumor suppressor cylindromatosis protein (CYLD) regulates NF-κB and JNK signaling pathways by cleaving K63-linked poly-ubiquitin chain from its substrate molecules and thus preventing the progression of tumorigenesis and metastasis of the cancer cells. Mutations in CYLD can cause aberrant structure and abnormal functionality leading to tumor formation. In this study, we utilized several computational tools such as PANTHER, PROVEAN, PredictSNP, PolyPhen-2, PhD-SNP, PON-P2, and SIFT to find out deleterious nsSNPs. We also highlighted the damaging impact of those deleterious nsSNPs on the structure and function of the CYLD utilizing ConSurf, I-Mutant, SDM, Phyre2, HOPE, Swiss-PdbViewer, and Mutation 3D. We shortlisted 18 high-risk nsSNPs from a total of 446 nsSNPs recorded in the NCBI database. Based on the conservation profile, stability status, and structural impact analysis, we finalized 13 nsSNPs. Molecular docking analysis and molecular dynamic simulation concluded the study with the findings of two significant nsSNPs (R830K, H827R) which have a remarkable impact on binding affinity, RMSD, RMSF, radius of gyration, and hydrogen bond formation during CYLD-ubiquitin interaction. The principal component analysis compared native and two mutants R830K and H827R of CYLD that signify structural and energy profile fluctuations during molecular dynamic (MD) simulation. Finally, the protein-protein interaction network showed CYLD interacts with 20 proteins involved in several biological pathways that mutations can impair. Considering all these in silico analyses, our study recommended conducting large-scale association studies of nsSNPs of CYLD with cancer as well as designing precise medications against diseases associated with these polymorphisms.

Cell cycle associated miRNAs as target and therapeutics in lung cancer treatment.

Lung cancer is the primary cause of cancer related deaths worldwide. Limited therapeutic options and resistance to existing drugs are the major hindrances to the clinical success of this cancer. In the past decade, several studies showed the role of microRNA (miRNA) driven cell cycle regulation in lung cancer progression. Therefore, these small nucleotide molecules could be utilized as promising tools in lung cancer therapy. In this review, we highlighted the recent advancements in lung cancer therapy using cell cycle linked miRNAs. By highlighting the roles of the specific cell cycle core regulators affiliated miRNAs in lung cancer, we further outlined how these miRNAs can be explored in early diagnosis and treatment strategies to prevent lung cancer. With the provided information from our review, more medical efforts can ensure a potential breakthrough in miRNA-based lung cancer therapy.

MicroRNAs expression analysis shows key affirmation of Synaptopodin-2 as a novel prognostic and therapeutic biomarker for colorectal and cervical cancers.

MicroRNAs play a crucial role in tumorigenesis, tumor progression, and metastasis, and thus they contribute in development of different malignancies including cervical cancer (CC) and colorectal cancer (CRC). Through integrated strategies of computational biology, this study aims to identify prognostic biomarkers responsible for CRC and CC prognosis, and potential therapeutic agents to halt the progression of these cancers. Expression analysis of miRNA datasets of CRC and CC identified 17 differentially expressed miRNAs (DEMs). SYNPO2, NEGR1, FGF7, LIFR, RUNX1T1, CFL2, BNC2, EPHB2, PMAIP1, and CDC25A differentially expressed genes (DEGs) regulated by these DEMs were classified as candidate genes responsible for CRC and CC. Down-regulation of Synaptopodin-2 (SYNPO2) is involved in emergence and progression of these cancers by activating ER, PI3K/AKT, and EMT pathways as well as by suppressing DNA damage response, and cell cycle pathways. Higher methylation rate in promoter region of SYNPO2 could be a possible reason for lowering the expression of SYNPO2 in tumor stages. Hence, the lower expression of SYNPO2 is associated with poor prognosis of CRC and CC and could function as prognostic biomarker and therapeutic target. Fourteen transcription factors were recognized which can activate/inhibit the transcription of SYNPO2 and may be a potential target to regulate expression of SYNPO2 in CRC and CC. Retinoic acid and Estradiol were identified as putative therapeutic drugs for CRC and CC patients. This study will thus help in understanding the underlying molecular events in CRC and CC that may improve the detection of malignant lesions in primary screening and will broaden the clinical applications.