KIF15在肿瘤中的研究进展

驱动蛋白家族成员15(kinesin family member 15,KIF15)是驱动蛋白超家族的一员,在有丝分裂和神经元发育中发挥重要作用,近年来关于KIF15在肿瘤中的研究逐渐增多。KIF15在多种恶性肿瘤中高表达,例如肺癌、胰腺癌、肝细胞癌等,且与患者的不良预后密切相关。此外,相关研究通过体内体外实验证实KIF15通过不同信号转导通路发挥促癌作用。虽然具体分子机制尚未完全明确,但KIF15有望成为恶性肿瘤药物治疗新靶点。本文就KIF15的结构、功能及其在肿瘤中的作用做一综述。

KIF15, a key regulator of nasopharyngeal carcinoma development mediated by the P53 pathway

Background:Kinesin family member 15(KIF15)is a protein that regulates cell mitosis and plays an important role in the development and progression of several types of human cancers.However,the role of KIF15 in the development of nasopharyngeal cancer(NPC)is still unclear.Methods:The differential expression of KIF15 in NPC and para-carcinoma tissues was evaluated based on data collected from Gene Expression Omnibus(GEO)database and immunohistochemical analysis of clinical specimens collected from a patient cohort.Cell lines 5-8F and CNE-2Z were selected for the construction of KIF15‑knockdown cell models.CCK8 assay,flow cytometry,wound healing,Transwell and clone formation assays were used to detect the proliferation,apoptosis,migration,invasion and colony formation of NPC cells in vitro.A mouse xenograft model and the tail intravenous mouse distant transfer model were constructed for in vivo study.Furthermore,the potential molecular mechanisms underlying the effects of KIF15 were explored through western blot analysis,and several in vitro and in vivo functional assays were performed to explore its role in NPC.Results:The results revealed significantly higher expression of KIF15 in NPC tissues compared to para-carcinoma tissues.High levels of KIF15 expression were also associated with short overall survival(OS)and progression-free survival(PFS).Knockdown of the KIF15 gene led to a cell cycle arrest in the growth 2(G2)phase,inhibition of cell proliferation,migration,invasion,colony formation,and enhanced cell apoptosis.The in vivo murine xenograft experiments showed that down-regulation of the KIF15 gene could inhibit tumor growth and reduce the risk of liver and lung metastasis in NPC.Moreover,the evaluation of the molecular pathway showed that the mitogen-activated protein kinase/P53 pathways might be involved in the KIF15-induced regulation of NPC.Rescue assays indicated that Pifithrin-αcould counteract the pro-proliferative and pro-apoptotic effects mediated by KIF15.Conclusion:This work indicated that KIF15 overexpression accelerated the progression of NPC and promoted the development of distant metastases.Therefore,KIF15 may have an important role as a prognostic indicator and a potential drug target for the treatment of NPC.

Anti-aging Effects of Alu Antisense RNA on Human Fibroblast Senescence Through the MEK-ERK Pathway Mediated by KIF15

Objective:To investigate whether human short interspersed nuclear element antisense RNA(Alu antisense RNA;Alu asRNA)could delay human fibroblast senescence and explore the underlying mechanisms.Methods:We transfected Alu asRNA into senescent human fibroblasts and used cell counting kit-8(CCK-8),reactive oxygen species(ROS),and senescence-associated beta-galactosidase(SA-β-gal)staining methods to analyze the anti-aging effects of Alu asRNA on the fibroblasts.We also used an RNA-sequencing(RNA-seq)method to investigate the Alu asRNA-specific mechanisms of anti-aging.We examined the effects of KIF15 on the anti-aging role induced by Alu asRNA.We also investigated the mechanisms underlying a KIF15-induced proliferation of senescent human fibroblasts.Results:The CCK-8,ROS and SA-β-gal results showed that Alu asRNA could delay fibroblast aging.RNA-seq showed 183 differentially expressed genes(DEGs)in Alu asRNA transfected fibroblasts compared with fibroblasts transfected with the calcium phosphate transfection(CPT)reagent.The KEGG analysis showed that the cell cycle pathway was significantly enriched in the DEGs in fibroblasts transfected with Alu asRNA compared with fibroblasts transfected with the CPT reagent.Notably,Alu asRNA promoted the KIF15 expression and activated the MEK-ERK signaling pathway.Conclusion:Our results suggest that Alu asRNA could promote senescent fibroblast proliferation via activation of the KIF15-mediated MEK-ERK signaling pathway.

KIF15 expression characteristics: Relevance toneo-adjuvant chemotherapy efficacy in breast cancer

Objective The relationship between the expression of kinesin family member 15 (KIF15) andclinicopathological features in breast cancer (BC) remains controversial. In this study, we aimed to explorethe influence of KIF15 expression on the efficacy of neoadjuvant chemotherapy (NAC) and evaluate itsclinical value in predicting prognosis for BC patients.Methods Immunohistochemistry was used to detect KIF15 expression in 93 BC patients undergoingNAC to analyze the relationship between KIF15 expression and clinical efficacy and analytical parameters.Results Of the 93 BC patients enrolled, 24.73% who underwent NAC had higher KIF15 expression levels,showing positive correlations with ER, HER-2, Ki67, and lymph node metastasis (P < 0.05). The clinicalbenefit of NAC was 70.97%, and the major histological response (MHR) rate was 61.29%. The effectivetherapeutic rate in patients with high KIF15 expression was 95.65%, while the MHR rate was 65.22%.Various molecular BC subtypes with varied clinical and pathological responses exhibited correlation toa large extent. Of all the BC patients studied, 84% of the triple-negative breast cancer (TNBC) patientswere evaluated as clinically effective, and 52% of the TNBC patients were evaluated as pathologicallyeffective, and these values were significantly higher than those of the other molecular types (P < 0.05).The expression of KIF15 in 25 TNBC patients showed positive correlations with lymph node metastasis.Conclusion Overexpression of KIF15 was shown to increase BC sensitivity to chemotherapy anddemonstrated better outcomes.

基于TCGA和CGGA数据库探究KIF15在胶质瘤中的表达及临床意义

目的 通过挖掘美国癌症基因图谱计划(TCGA)和中国脑胶质瘤基因图谱计划(CGGA)中胶质瘤基因谱数据库,分析KIF15在胶质瘤中的表达及临床意义。 方法 通过人类蛋白数据库探究KIF15在神经系统中的表达特征。获取TCGA和CGGA中胶质瘤患者肿瘤样本全基因转录组(mRNAseq)数据,分析KIF15在不同级别和病理类型胶质瘤中的转录水平差异,及其与患者中位生存期的关系。通过胶质瘤标本芯片进行KIF15的免疫组织化学染色,分析KIF15在胶质瘤不同级别中的蛋白水平差异,通过转录组数据分析KIF15与肿瘤增殖指标Ki67的相关性,并通过差异基因(DEGs)进行基因本体(GO)分析和信号通路富集(KEGG)分析探讨KIF15在胶质瘤中参与调控的分子信号通路。 结果 在中枢神经系统大脑中,各部位组织可检测到KIF15的蛋白水平和转录水平均较低。TCGA和CGGA转录组数据分析显示,胶质瘤WHO级别越高,KIF15的mRNA水平显著增高,WHO Ⅳ级相较于WHO Ⅱ级和Ⅲ级,差异有统计学意义(P<0.05);并且,在胶质母细胞瘤中KIF15的mRNA水平最高,相比较于星形胶质细胞、少突胶质细胞瘤、少突星形胶质细胞瘤、间变性星形胶质细胞瘤、间变性少突胶质细胞瘤,差异均有统计学意义(P<0.05)。KIF15高水平组患者的中位生存期较KIF15低水平组更短,差异有统计学意义(P<0.05)。胶质瘤组织芯片染色结果显示,WHO级别越高,胶质瘤组织染色强度评分趋向更高,WHO Ⅳ级胶质瘤评分以2、3分为主,而WHO Ⅱ级以0、1分为主。KIF15和Ki67的mRNA水平之间为显著性正相关关系,在TCGA转录组数据和CGGA转录组数据库中r值分别为0.725、0.706。TCGA转录组数据共筛选到707个DEGs,KIF15高水平组相比较于KIF15低水平组,表达水平升高的DEGs有328个,表达水平降低的DEGs有379个。GO分析显示这些DEGs参与的生物学过程前10位包括有细胞周期转换和细胞有丝分裂调控。分子信号通路KEGG分析显示DEGs参与的分子信号通路包括细胞周期、P53通路和DNA复制。 结论 KIF15在胶质瘤中高表达,并且高水平KIF15预示胶质瘤恶性程度高,患者生存期较差。KIF15参与调控了肿瘤细胞周期通路,可能是一个潜在的胶质瘤基因治疗靶点。

Functional role of circRNA CHRC through miR-431-5p/KLF15 signaling axis in the progression of heart failure

Pathological myocardial hypertrophy is a common early clinical manifestation of heart failure,with noncoding RNAs exerting regulatory influence.However,the molecular function of circular RNAs(circRNAs)in the progression from cardiac hypertrophy to heart failure remains unclear.To uncover functional circRNAs and identify the core circRNA signaling pathway in heart failure,we construct a global triple network(microRNA,circRNA,and mRNA)based on the competitive endogenous RNA(ceRNA)theory.We observe that cardiac hypertrophy-related circRNA(circRNA CHRC),within the ceRNA network,is down-regulated in both transverse aortic constriction mice and Ang-II--treated primary mouse cardiomyocytes.Silencing circRNA CHRC increases cross-sectional cell area,atrial natriuretic peptide,andβ-myosin heavy chain levels in primary mouse cardiomyocytes.Further screening shows that circRNA CHRC targets the miR-431-5p/KLF15 axis implicated in heart failure progression in vivo and in vitro.Immunoprecipitation with anti-Ago2-RNA confirms the interaction between circRNA CHRC and miR-431-5p,while miR-431-5p mimics reverse Klf15 activation caused by circRNA CHRC overexpression.In summary,circRNA CHRC attenuates cardiac hypertrophy via sponging miR-431-5p to maintain the normal level of Klf15 expression.