Background/Objectives:FAM72B (Family with sequence similarity 72 member B) is a gene whose function is not yet fully elucidated and which belongs to the FAM72 gene family. Recent studies have indicated that it is involved in the regulation of stem cell proliferation and DNA repair and serves as a valuable prognostic biomarker for a few types of cancer. This study aimed to systematically investigate the expression profile of FAM72B in pan-cancer, its role in the tumor immune microenvironment, and its potential as a prognostic and immunotherapeutic biomarker. Methods: Using bioinformatics tools such as SangerBox3.0, GEPIA2.0, Kaplan-Meier Plotter, and cBioPortal, we systematically analyzed the correlation of FAM72B expression levels with various cancer types, clinical pathological parameters, prognostic value, genetic mutations, genomic heterogeneity, immune checkpoint genes, immune cell infiltration levels, and single-cell-level characteristics. Results:FAM72B was found to be overexpressed in most cancers and significantly associated with poor prognosis, although it may exert a protective effect in some cancers like thymoma (THYM). Its expression level was positively correlated with tumor mutation burden (TMB), microsatellite instability (MSI), neoantigen (NEO) levels, and expression of immune checkpoint genes in most cancers, suggesting that patients with high FAM72B expression may respond better to immune checkpoint inhibitors. Moreover, FAM72B expression was significantly correlated with the infiltration levels of various immune cells in the tumor immune microenvironment across pan-cancer. Single-cell sequencing results also demonstrated a significant correlation between FAM72B and the biological functional states of multiple cancers. Conclusions:FAM72B holds promise as a potential pan-cancer prognostic biomarker and therapeutic target, providing a novel basis for the development of personalized treatment strategies.

There is an urgent need to develop antibiotics with new mechanisms of action for combating antibiotic-resistant bacteria, particularly against Gram-negative pathogens that severely threaten human health. Here, we introduce the rational design and comprehensive characterization of self-derived antibacterial peptides that specifically target Escherichia coli BamA and BamD, vital components of the β-barrel assembly machine (BAM) for the folding and membrane integration of outer membrane proteins (OMPs) in Gram-negative bacteria. Among the three BamA-targeted peptides, BamA543-551, which corresponds to an extracellular loop of BamA, exhibits remarkable bactericidal activity against OM-permeabilizedE. coli cells. Similarly, among four BamD-targeted peptides, BamD163-187 corresponding to a BamA-interacting α-helix exhibits potent bactericidal activity. Notably, both BamA543-551 and BamD163-187 are able to kill other OM-permeabilized Gram-negative pathogens but not Gram-positive ones, and fusion with a cell membrane-penetrating peptide enabled them to directly kill intactE. coli cells. Further, both of them significantly change the cell membrane integrity ofE. coli, induce the accumulation of misfolded OmpF, and reduce the level of folded OmpF. In particular, in vivo photo-cross-linking analysis indicates that BamA543-551 disrupts the direct interaction between BamA and periplasmic chaperone SurA in livingE. coli cells, thus offering insights into their mode of action. Collectively, our findings confirm the potential of BamA and BamD as promising antibiotic targets and suggest that BamA- and BamD-derived peptides can be candidates for antibiotic development.

Disulfidptosis is a newly discovered mode of cell death induced by disulfide stress. However, the prognostic value of disulfidptosis-related genes (DRGs) in renal cell carcinoma (RCC) remains to be further elucidated. In this study, consistent cluster analysis was used to classify 571 RCC samples into three DRG-related subtypes based on changes in DRGs expression. Through univariate regression analysis and LASSO-Cox regression analysis of differentially expressed genes (DEGs) among three subtypes, we constructed and validated a DRG risk score to predict the prognosis of patients with RCC, while also identifying three gene subtypes. Analysis of DRG risk score, clinical characteristics, tumor microenvironment (TME), somatic cell mutations, and immunotherapy sensitivity revealed significant correlations between them. A series of studies have shown that MSH3 can be a potential biomarker of RCC, and its low expression is associated with poor prognosis in patients with RCC. Last but not least, overexpression of MSH3 promotes cell death in two RCC cell lines under glucose starvation conditions, indicating that MSH3 is a key gene in the process of cell disulfidptosis. In summary, we identify potential mechanism of RCC progression through DRGs -related tumor microenvironment remodeling. In addition, this study has successfully established a new disulfidptosis-related genes prediction model and discovered a key gene MSH3. They may be new prognostic biomarkers for RCC patients, provide new insights for the treatment of RCC patients, and may inspire new methods for the diagnosis and treatment of RCC patients.

Multiple myeloma (MM) is a clonal disease of plasma cells that remains, for the most part, incurable despite the advent of several novel therapeutics. The elevated expression of p27 and its association with cell-cycle arrest is speculated to be one of the major mechanisms by which MM cells escape the cytotoxic effects of therapeutic agents. In this study, we demonstrated that RBX1 silencing could inhibit MM cell growth and promote cell drug resistance. RBX1 directly interacted with and triggered the ubiquitination and degradation of p27, ultimately causing p27 reduction. Additionally, cell growth and apoptosis analysis indicated that the role of RBX1 in regulating myeloma cell proliferation and drug resistance resulted from p27 accumulation, which occurred in a Thr187 phosphorylation-dependent manner. Furthermore, the cell-cycle analysis demonstrated that RBX1 overexpression induced cells to enter the cell cycle (S-phase) and partially inhibited chemotherapeutic drugs-mediated cell cycle arrest. Notably, the forced expression of RBX1 also inhibited the cell adhesion-mediated elevation of p27 and induced the accumulation of adherent cells in apoptosis, especially the proteolytic cleavage of caspase-3. Additionally, RBX1 knockdown significantly inhibited myeloma development in SCID-Hu mice and in a human MM xenotransplant model. Overall, these in vitro and in vivo experiments indicated that the RBX1-p27 axis could be a central molecular mechanism by which RBX1 functions as a tumor promoter and stimulates cell growth in chemotherapeutic drugs treated MM cells.

Despite the continuous improvement of various therapeutic techniques, the overall prognosis of tumors has been significantly improved, but malignant tumors in the middle and advanced stages still cannot be completely cured. It is now evident that cell adhesion-mediated resistance (CAM-DR) limits the success of cancer therapies and is a great obstacle to overcome in the clinic. The interactions between tumor cells and extracellular matrix (ECM) molecules or adjacent cells may play a significant role in initiating the intracellular signaling pathways that are associated with cell proliferation, survival upon binding to their ligands. Recent studies illustrate that these adhesion-related factors may contribute to the survival of cancer cells after chemotherapeutic therapy, advantageous to resistant cells to proliferate and develop multiple mechanisms of drug resistance. In this review, we focus on the molecular basis of these interactions and the main signal transduction pathways that are involved in the enhancement of the cancer cells’ survival. Furthermore, therapies targeting interactions between cancer cells and their environment to enhance drug response or prevent the emergence of drug resistance will also be discussed.

Several lines of evidence show that RUNX2 as a transcription factor is closely involved in carcinogenesis in a variety of human cancers. Cell adhesion-mediated drug resistance (CAM-DR) is an important part of the mechanism underlying drug resistance in hematological tumors. In this study, we investigated the biological function of RUNX2 in B-cell Non-Hodgkin’s lymphoma (B-NHL) and multiple myeloma (MM). We assessed the expression of RUNX2 in suspension and adhesion model by western blot in B-NHL and MM. Adhesion assay, flow cytometry and CCK-8 were utilized to examine the role and mechanism of RUNX2 in CAM-DR and proliferation in B-NHL and MM. RUNX2 was highly expressed in adherent B-NHL and MM cells compared to suspension cells, and knockdown the expression of RUNX2 could reverse CAM-DR. Besides, RUNX2 could promote the proliferation of B-NHL and MM cells. Furthermore, RUNX2 participated the process of CAM-DR and proliferation by regulating the AKT/GSK-3β pathway. Developing RUNX2 inhibitor may be a possible strategy for drug resistance.

目的:探究热休克转录因子1(heat shock factor1,HSF1)在硼替佐米(bortezomib,BTZ)诱导的多发性骨髓瘤细胞凋亡中的作用及机制.方法:利用BTZ刺激骨髓瘤细胞RPMI 8226及U266,核浆分离检测HSF1分别在骨髓瘤细胞胞核、胞质的表达;利用发卡RNA抑制HSF1表达,并结合BTZ刺激骨髓瘤细胞,检测其表达对骨髓瘤细胞增殖、细胞凋亡的影响;最后构建骨髓瘤细胞体外黏附培养模型,进一步验证HSF1表达对骨髓瘤细胞凋亡的影响.结果:BTZ作用骨髓瘤细胞过程中,HSF1向胞核分布显著增加;HSF1低表达可以促进BTZ诱导的骨髓瘤细胞凋亡;利用HSF1抑制剂处理骨髓瘤细胞验证了上述结果;利用骨髓基质细胞HS-5与骨髓瘤细胞共培养,抑制HSF1表达可以显著增加BTZ诱导的骨髓瘤细胞死亡数量.结论:BTZ刺激骨髓瘤细胞可以诱导HSF1胞核表达,HSF1表达上调可以促进BTZ诱导的骨髓瘤细胞凋亡.

Diffuse large B cell lymphoma (DLBCL), a heterogeneous group of invasive disease, is the most common type of B-cell non-Hodgkin's lymphomas. The mechanism of its development is closely related to the constitutive activation of NF-κB. In this study, we investigated the function and the mechanism of β-TRCP1 in DLBCL. CCK8 and EdU assays showed that β-TRCP1 could promote the growth of DLBCL cells under the stimulation of TNFα. Furthermore, overexpression of β-TRCP1 enhanced NF-κB activation in the presence of TNFα. Moreover, ectopic expression of β-TRCP1 decreased IκB-α expression but increased phospho-p65 expression. In addition, β-TRCP1 promoted cell cycle progression by accelerating G1-S phase transition. We also found that silencing of β-TrCP1 increased mitoxantrone-induced cell growth arrest and apoptosis. Based on these, we proposed that the expression of β-TRCP1 promoted cell proliferation via TNF-dependent NF-κB activation in DLBCL cells.

Exposure of cells to bortezomib (BTZ) could activate heat shock protein (HSP) expression, which is regulated mainly by heat shock factor 1 (HSF1). We determined the role of Apg-1 (HSPA4L, a member of the HSP110 family) in HSF1 activation and bortezomib sensitivity by silencing HSF1 in multiple myeloma (MM) cells. We observed that the Apg-1 protein level was upregulated as BTZ concentration increased. To investigate the mechanism underlying Apg-1 induction, we evaluated the HSF1 translocation and found BTZ-inducible transposition to the nucleus of HSF1. In addition, cleaved caspase 3 and PARP might account for increased BTZ sensitivity on Apg-1 silencing. Furthermore, silencing HSF1 with shRNA or triptolide resulted in significant BTZ sensitivity. It had a more profound effect on cell death caused by BTZ when myeloma cells were adherent to bone marrow stromal cell lines (Hs-5). In summary, we found that Apg-1 knockdown sensitized myeloma cells to bortezomib treatment, which may provide a new approach in multiple myeloma treatment.

Background Cell adhesion-mediated drug resistance (CAM-DR) is a major clinical problem that prevents successful treatment of multiple myeloma (MM). In particular, the expression levels of integrin β1 and its sub-cellular distribution (internalization and trafficking) are strongly associated with CAM-DR development. Methods Development of an adhesion model of established MM cell lines and detection of Numbl and Integrinβ1 expression by Western Blot analysis. The interaction between Numbl and Integrinβ1 was assessed by a co-immunoprecipitation (CO-IP) method. Calcein AM assay was performed to investigate the levels of cell adhesion. Finally, the extent of CAM-DR in myeloma cells was measured using cell viability assay and flow cytometry analysis. Results Our preliminary date suggest that Numbl is differentially expressed in a cell adhesion model of MM cell lines. In addition to binding to the phosphotyrosine-binding (PTB) domain, the carboxyl terminal of Numbl can also interact with integrin β1 to regulate the cell cycle by activating the pro-survival PI3K/AKT signaling pathway. This study intends to verify and elucidate the interaction between Numbl and integrin β1 and its functional outcome on CAM-DR. We have designed and developed a CAM-DR model using MM cells coated with either fibronectin or bone marrow stromal cells. We assessed whether Numbl influences cell-cycle progression and whether it, in turn, contributes to activation of PI3K/AKT signal pathway through the adjustment of its carboxyl end. Finally, we showed that the interaction of Numbl with integrin β1 promotes the formation of CAM-DR in MM cells. Conclusions Our findings elucidated the specific molecular mechanisms of CAM-DR induction and confirmed that Numbl is crucial for the development of CAM-DR in MM cells.

LIM domains-containing protein 1 (LIMD1) is a tumor suppressor protein downregulated in numerous solid malignancies. However, the functional role of LIMD1 in non-Hodgkin's lymphoma (NHL) remains unclear. In the present study, it was demonstrated that LIMD1 is associated with the proliferation of NHL and cell adhesion mediated-drug resistance (CAM-DR). It was indicated by western blot analysis that LIMD1expression is lower in progressive lymphoma compared with indolent lymphoma. Furthermore, it was indicated that the role of LIMD1 in cell viability and proliferation remains unclear. Finally, the present study demonstrated that LIMD1 serves an important role in CAM-DR by regulating cell cycle progression. Silencing of LIMD1 may reverse CAM-DR in NHL. Therefore, the findings of the present study suggested that LIMD1 may be a potential therapeutic target for patients with NHL.

[This corrects the article DOI: 10.21037/atm.2019.11.105.].

Tripartite motif containing 28 (TRIM28) as a transcriptional co-repressor has been reported playing a role in regulating DNA damage response (DDR), cell differentiation, immune response, and tumorigenesis. The present study was performed to explore the biological function and clinical significance of TRIM28 in B-cell non-Hodgkin lymphoma (B-NHL). Results of the study displayed that high expression of TRIM28 was positively associated with the poorer survival of B-NHL patients as an independent prognostic factor. In addition, TRIM28 could promote the B-NHL cells proliferation through modulating cell cycle progression. The change of cyclinA, P21, and PCNA expression after TRIM28 expression modified further illustrated the mechanism in which TRIM28 participated in cell proliferation progression. Moreover, inhibition TRIM28 expression in B-NHL cells enhanced the sensibility to Bortezomib by regulating p53-mediated apoptosis pathway. Taken together, the present study showed that TRIM28 functions as a tumor promoter in B-NHL and may be a novel target for drug resistance to Bortezomib.

Neuroinflammation mediated by NLRP-1 inflammasome plays an important role in the pathogenesis of neurodegeneration diseases such as Alzheimer's disease (AD). Chronic glucocorticoids (GCs) exposure has deleterious effect on the structure and function of neurons and was found to be correlated with development and progression of AD. We hypothesize that chronic glucocorticoids may down-regulate the expression of glucocorticoids receptor (GR) and activate NLRP-1 inflammasome in hippocampal neurons, which may promote neuroinflammation and induce neuronal injury. The present results showed that chronic DEX exposure significantly increased LDH release and apoptosis, decreased MAP2 and GR expression in hippocampal neurons. DEX (5 μΜ) exposure for 3 d significantly increased the expression of NLRP-1, ASC, caspase-1 and IL-1β in the hippocampal neurons and the release of IL-1β and IL-18 in the supernatants. Moreover, DEX (1, 5 μΜ) treatment for 3 d significantly increased the expression of NF-κB in hippocampal neurons. The GR antagonist, mifepristone (RU486), had protective effects on chronic DEX induced hippocampal neurons injury and NLRP1 inflammasome activation. The results suggest that chronic GCs exposure can decrease GR expression and increase neuroinflammation via NLRP1 inflammasome and promote hippocampal neurons degeneration, which may play an important role in the progression and development of AD.

Acid-sensing ion channels, a proton-gated cation channel, can be activated by low extracellular pH and involved in pathogenesis of some tumors such as glioma and breast cancer. However, the role of acid-sensing ion channels in the growth of lung cancer cell is unclear. In this study, we investigated the expression of acid-sensing ion channels in human lung cancer cell line A549 and their possible role in proliferation and migration of A549 cells. The results show that acid-sensing ion channel 1, acid-sensing ion channel 2, and acid-sensing ion channel 3 are expressed in A549 cells at the messenger RNA and protein levels, and acid-sensing ion channel–like currents were elicited by extracellular acid stimuli. Moreover, we found that acidic extracellular medium or overexpressing acid-sensing ion channel 1a promotes proliferation and migration of A549 cells. In addition psalmotoxin 1, a specific acid-sensing ion channel 1a inhibitor, or acid-sensing ion channel 1a knockdown can abolish the effect of acid stimuli on A549 cells. In addition, acid-sensing ion channels mediate increase of [Ca 2+ ] i induced by low extracellular pH in A549 cells. All these results indicate that acid-sensing ion channel–calcium signal mediate lung cancer cell proliferation and migration induced by extracellular acidosis, and acid-sensing ion channels may serve as a prognostic marker and a therapeutic target for lung cancer.

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Chromodomain helicase/ATPase DNA binding protein 1-like (CHD1L) gene is a newly identified oncogene located at Chr1q21 and it is amplified in many solid tumors. In this study, we intended to investigate the clinical significance of CHD1L expression in human glioma and its biological function in glioma cells. Western blot and immunohistochemistry analysis showed that CHD1L was overexpressed in glioma tissues and glioma cell lines. In addition, the expression level of CHD1L was positively correlated with glioma pathological grade and Ki-67 expression. Kaplan–Meier curve indicated that high expression of CHD1L may result in poor prognosis of glioma patients. Accordingly, suppression of CHD1L in glioma cells was shown to induce cell cycle arrest and increase apoptosis. In addition, knockdown of CHD1L significantly accelerated migration and invasion ability of glioma cells. Together our findings suggest that CHD1L is involved in the progression of glioma and may be a novel target for further therapy.

DIX domain containing 1 (DIXDC1), is a human homolog of Ccd1, a DIX domain containing protein in zebrafish. The present study was undertaken to determine the expression and biologic function of DIXDC1 in Non-Hodgkin's lymphoma (NHL). Clinically, we detected that the expression of DIXDC1 was significantly lower in the indolent lymphomas compared with the progressive lymphomas by immunohistochemistry analysis. Functionally, we found that DIXDC1 could promote cell proliferation via modulating cell cycle progression and PI3K/AKT signaling pathway in NHLs. Moreover, we confirmed that DIXDC1 was involved in the process of lymphoma cell adhesion mediated drug resistance (CAM-DR). Adhesion to fibronectin (FN) or HS-5 up-regulated DIXDC1 expression, and up-regulation of DIXDC1 resulted in an increased expression of p-AKT, which promoted CAM-DR. Our finding supports the role of DIXDC1 in cell proliferation, cell cycle and CAM-DR in NHLs. We propose that inhibition of DIXDC1 expression may be a novel therapeutic approach for NHLs patients, and it may be a target for drug resistance.

Cell adhesion‑mediated drug resistance (CAM‑DR) remains a major obstacle to the effectiveness of chemotherapeutic treatment of lymphoma. Far upstream element binding protein 1 (FBP1) is a multifunctional protein that is highly expressed in proliferating cells of several solid neoplasms; however, its expression and biological function in B‑cell lymphoma is largely unknown. FBP1 expression in both reactive lymphoid tissues and several B‑cell lymphomas, including follicular lymphoma and diffuse large B‑cell lymphoma were detected by immunohistochemistry analysis. FBP1 expression in B‑cell lymphoma was also associated with poor survival outcomes. Functionally, small interfering RNA‑mediated silencing of FBP1 was able to inhibit the proliferation of B‑cell lymphoma cells, resulting in G0/G1 phase cell cycle arrest. Furthermore, results of a cell adhesion assay demonstrated that adhesion to fibronectin or bone marrow stromal cells induced FBP1 expression, which in turn facilitated cell adhesion. Finally, FBP1 knockdown reversed CAM‑DR. These findings support a role for FBP1 in non‑Hodgkin lymphoma cell proliferation, adhesion and drug resistance, and may lead to the generation of a novel therapeutic approach targeting this molecule.

Previous studies have shown that chromodomain helicase/ATPase DNA binding protein 1-like gene (CHD1L) exerts its anti-apoptotic function in many solid cancers. However, its role in human multiple myeloma (MM) has not been thoroughly elucidated. In this study, we investigate the role of CHD1L in MM. Preliminarily, up-regulation and down-regulation assay verified that CHD1L exerts its anti-apoptotic role through the apoptotic pathway involving caspase-9-caspase-3 apoptotic pathway in MM cells. In addition, we determined that CHD1L expression is increased when MM cells were adhered to fibronectin (FN) or bone marrow stromal cell line HS-5 cells and cell adhesion assay indicated that CHD1L siRNA reversed the high cell adhesion rate. Consistent with the reduced adhesion rate, the cells translated to a compromised cell adhesion-mediated drug resistance (CAM-DR) phenotype in MM. In summary, we will propose strategies for developing a CHD1L inhibitor for potential treatment of MM.