Unveiling the predictive power of bacterial response-related genes signature in hepatocellular carcinoma:with bioinformatics analyses and experimental approaches

Background:Despite progress in therapeutic strategies,treatment failure in hepatocellular carcinoma(HCC)remains a major challenge,resulting in low survival rates.The presence of bacteria and the host’s immune response to bacteria can influence the pathogenesis and progression of HCC.We developed a risk model based on bacterial response-related genes(BRGs)using gene sets from molecular signature databases to identify new markers for predicting HCC outcomes and categorizing patients into different risk groups.Methods:The data from the Cancer Genome Atlas(TCGA)portal was retrieved,and differentially expressed BRGs were identified.Uni-and multivariate Cox regression and least absolute shrinkage and selection operator(LASSO)LASSO analyses were executed to develop the prognostic risk model.Key contributor to the prognostic model was identified,and the results were tested by using experimental assays in HCC cell lines.Results:Multivariate analysis demonstrated an independent prognostic factor of 12-BRG signature in HCC patients.The low-risk group had better overall survival with significantly lower tumor mutation burden(TMB).The risk scores were negatively correlated with the presence of tumor-infiltrating immune cells.In an effort to find the key contributor of the 12-BRG signature,we found polo like kinase1(PLK1)had the best accuracy with 1-,3-,and 5-year AUC of 0.72,0.66,and 0.65,respectively.Both PLK1 inhibitor Volasertib and the knockdown of the PLK1 gene resulted in diminished viability in HCC cell lines.The combination of PLK1 inhibition with low-dose chemotherapy exhibited an amplified effect of the treatment.Conclusion:To date,there have been no reports of BRG biomarkers in HCC,and this study represents for the first time that a 12-BRG signature has the potential to predict the survival of HCC.

Anti-proliferative effects of a small molecule inhibitor of CDKAT7519 on chronic myeloid leukemia (CML) cells through haltingthe transition of cells from G2/M phase of the cell cycle

Pathogenesis of chronic myeloid leukemia(CML)has mostly been studied with regard to the oncogenic role of BCR/ABL fusion,however,recent disclosures have declared that the challenges with the treatment of CML patients would not be resolved until the role of other aberrancies is ignored.Given the involvement of cyclin-dependent kinases(CDKs)in the pathogenesis of CML,the present study aimed to investigate the effects of a multi-CDK inhibitor AT7519 on BCR/ABL-harboring CML-derived K562 cells.Our results showed that AT7519 effectively reduced the survival of K562 and induced its anti-proliferative effect through the induction of G2/M arrest due to elevated p21 and p27.The resulting data also revealed that either direct or indirect suppression of c-Myc using specific c-Myc inhibitor 10058-F4 and selective PI3K inhibitor CAL-101 resulted in a superior cytotoxicity,suggesting that the activation of PI3K pathway could attenuate antileukemic effects of the inhibitor,at least partly,through a c-Mycdependent mechanism.To the best of our knowledge,to date,no study has addressed the effect of autophagy on CML cell response to AT7519,and,herein,we proposed for the first time that the suppression of autophagy boosted AT7519 cytotoxicity against K562.Overall,we suggested that selective CDK inhibitor AT7519 exerted antileukemic effect against CML cells and propose a novel therapeutic application for the inhibitor either as a single agent or in combination with c-Myc and/or PI3K inhibitors.

Bone marrow microenvironment: The guardian of leukemia stem cells

Bone marrow microenvironment (BMM) is the main sanctuary of leukemic stem cells (LSCs) and protects these cells against conventional therapies. However, it may open up an opportunity to target LSCs by breaking the close connection between LSCs and the BMM. The elimination of LSCs is of high importance, since they follow cancer stem cell theory as a part of this population. Based on cancer stem cell theory, a cell with stem cell-like features stands at the apex of the hierarchy and produces a heterogeneous population and governs the disease. Secretion of cytokines, chemokines, and extracellular vesicles, whether through autocrine or paracrine mechanisms by activation of downstream signaling pathways in LSCs, favors their persistence and makes the BMM less hospitable for normal stem cells. While all details about the interactions of the BMM and LSCs remain to be elucidated, some clinical trials have been designed to limit these reciprocal interactions to cure leukemia more effectively. In this review, we focus on chronic myeloid leukemia and acute myeloid leukemia LSCs and their milieu in the bone marrow, how to segregate them from the normal compartment, and finally the possible ways to eliminate these cells.