脂肪量和肥胖相关基因与恶性肿瘤的研究进展

脂肪量和肥胖相关（fat mass and obesity-associated,FTO）基因是全基因组关联分析中发现的第一个与普通人群肥胖相关的可靠候选基因,主要调节下游靶基因3′非翻译区的N6-甲基腺嘌呤（N6-methyladenosine,m6A）。近年来研究发现FTO基因不仅在肥胖相关疾病中发挥重要作用,还参与乳腺癌、子宫内膜癌、急性髓系白血病等多种恶性肿瘤的发生发展及预后。也有研究表明,FTO基因编码的蛋白是m6A修饰的重要组成部分,可调控肿瘤干细胞功能,促进癌细胞的生长和转移。本文就FTO基因与恶性肿瘤关系的研究进展作一综述。     

18α-甘草次酸对IHH-4细胞FTO表达及增殖、迁移的影响

目的:评价肥胖相关基因(fat mass and obesity associated gene，FTO)蛋白在人甲状腺乳头状癌IHH-4细胞中的表达、生物学作用及18α-甘草次酸（18α-Glycyrrhetinic acid，AGA）对该细胞FTO表达的影响。方法:体外培养IHH-4细胞，取对数生长期细胞进行实验；采用MTT和Transwell迁移实验评价不同浓度的AGA（80、160、320 μmol/L）对IHH-4细胞增殖和迁移能力的影响；通过RNA干扰(RNA interference，RNAi)技术沉默肥胖相关基因(fat mass and obesity associated gene，FTO)的表达；采用Western blot法评价AGA处理前后FTO、周期蛋白依赖性激酶4(cyclin-dependent kinase 4，CDK4)和Cofilin-1的表达。结果:不同浓度的AGA均能显著抑制IHH-4细胞的增殖及迁移，差异具有统计学意义（P<0.05）；IHH-4细胞高表达FTO、CDK4和Cofilin-1；RNAi下调IHH-4细胞FTO后导致CDK4和Cofilin-1表达水平显著降低（P<0.05），IHH-4细胞的增殖及迁移能力亦显著下降；AGA处理显著减少了IHH-4细胞中FTO、CDK4和Cofilin-1的表达水平（P<0.05）；经RNAi处理48 h的IHH-4细胞再加入AGA无法进一步降低FTO、CDK4和Cofilin-1的表达水平及增殖、迁移能力（P>0.05）。结论:FTO在促进人甲状腺乳头状癌细胞的增殖及迁移中具有重要作用；AGA通过控制FTO的表达抑制IHH-4细胞的增殖及迁移。     

长链非编码RNA调控肿瘤能量代谢重编程机制的研究进展

尽管目前普遍认为肿瘤细胞内存在能量代谢异常且影响肿瘤的生物学行为, 但能量代谢重编程的确切机制及对肿瘤细胞增殖、侵袭、转移影响的具体机制尚不明确。近年来, 有研究显示长链非编码RNA(lncRNA)在转录及转录后水平通过与特定核酸和蛋白结合, 能够特异性地通过转录干扰、基因的表观遗传调控、蛋白活性改变、竞争性结合microRNA(miRNA)等相关机制影响肿瘤细胞能量代谢和发生、发展。lncRNA调控肿瘤能量代谢重编程机制研究的不断深入有望为肿瘤诊断治疗开辟新的标志物和靶点。文章就目前lncRNA调控肿瘤葡萄糖、脂肪酸、蛋白质和核苷酸代谢重编程作用机制的研究进展作一综述, 以期为lncRNA调控能量代谢通路为靶向的抗肿瘤治疗提供新思路。     

胃癌中FTO表达与TGF-β表达、肿瘤免疫表型的关系及临床意义

目的:分析胃癌组织中FTO表达与TGF-β表达及肿瘤免疫表型的关系及临床意义。方法:采用TIMER数据库分析胃癌组织中FTO和TGF-β mRNA的表达情况。采用GEPIA数据库评估FTO及TGF-β mRNA在胃癌中表达的相关性。利用TIMER数据库分析FTO对胃癌免疫细胞浸润水平的影响。采用免疫组织法检测胃FTO、TGF-β、CD8+T细胞的表达,分析FTO与TGF-β、肿瘤免疫表型的相关性,及其与临床病理特征的关系。结果:胃癌组织中FTO、TGF-β阳性率皆高于癌旁组织(P＜0.05);分析三种免疫表型在胃癌中的表达情况,发现在胃癌组织中以免疫豁免型为主(P＜0.05);在胃癌中,FTO表达水平与TGF-β表达水平、免疫细胞浸润及免疫豁免型呈显著正相关(P＜0.05);FTO表达与淋巴结转移、TNM分期及分化程度密切相关(P＜0.05)。结论:FTO在胃癌中高表达,可影响TGF-β表达水平、免疫细胞浸润水平及肿瘤免疫表型。     

SIRT1基因在肿瘤中的作用机制

Ⅲ类去乙酰化酶Sirtuin 1(SIRT1)是一种依赖NAD+的组蛋白去乙酰化酶.研究发现SIRT1在肿瘤中的作用具有双面性,它可通过抑制炎症、肿瘤血管形成及与肿瘤相关基因相互作用等机制抑制肿瘤的发生发展;也可通过调控肿瘤相关基因、上皮间质转化、促进肿瘤细胞增殖和肿瘤放化疗耐受以及维持肿瘤干细胞的存活等机制促进肿瘤的增殖、侵袭和转移.     

RASSF1A基因甲基化与妇科肿瘤

ras相关区域家族1A基因(RASSF1A)启动子区域的高甲基化影响了该基因的转录表达,促进了相关肿瘤的发生发展.研究发现,RASSF1A启动子区域高甲基化与子宫颈癌、卵巢癌和子宫内膜癌等的发生密切相关.     

微RNA对肿瘤干细胞自我更新的影响机制

肿瘤干细胞( CSC)的自我更新与肿瘤的形成、复发以及耐药有关.微RNA (miRNA)能够调控细胞周期,影响细胞命运.目前的研究已发现微RNA可通过直接调节相关的基因靶点作用于肿瘤干细胞的自我更新,同时可能通过影响Wnt、Notch、Hedgehog等信号传导途径参与调节肿瘤干细胞自我更新.     

微RNA对肿瘤干细胞自我更新的影响机制

肿瘤干细胞( CSC)的自我更新与肿瘤的形成、复发以及耐药有关.微RNA (miRNA)能够调控细胞周期,影响细胞命运.目前的研究已发现微RNA可通过直接调节相关的基因靶点作用于肿瘤干细胞的自我更新,同时可能通过影响Wnt、Notch、Hedgehog等信号传导途径参与调节肿瘤干细胞自我更新.     

乳腺癌患者外周血清中APC基因启动子甲基化异常的检测及其意义

背景与目的:检测肿瘤患者外周血中肿瘤相关标志物是当前肿瘤研究的热点之一,恶性肿瘤患者外周血中存在游离的肿瘤相关DNA已引起肿瘤学界的极大关注,人们曾在多种肿瘤患者血清中发现与原发肿瘤相同的DNA变异.本研究以APC(adenomatous polyposis coli)基因启动子甲基化作为肿瘤标志物,探讨乳腺癌患者外周血清中游离的肿瘤相关DNA与肿瘤组织及临床病理参数的相关性.方法:采用甲基化特异性PCR(methylation specific-PCR,MSP)方法,分别检测84例乳腺癌组织、癌旁正常腺体组织及外周血清中游离DNA APC基因启动子甲基化状况.结果:84例乳腺癌组织APC基因启动子甲基化频率为45.2%(38/84),相应外周血清中同样DNA变异阳性检出率为31.0%(26/84).外周血清中DNA甲基化变异与肿瘤组织的甲基化状况显著相关(r=0.977,P=0.002).检测外周血清中APC基因甲基化的敏感性为68.4%,特异性为97.8%.肿瘤组织及外周血清中游离DNA甲基化异常与临床分期、病理类型、肿块大小及受体状况无相关性(P＞0.05).肿瘤组织未检测到甲基化患者的血清中及健康人血清中均未检测到该基因甲基化变异.结论:乳腺癌患者外周血清中肿瘤相关DNA甲基化与肿瘤组织中相同基因的变异显著相关.     

OTUB1在肿瘤中的研究进展

OTUB1属于去泛素化酶家族成员之一,与多种恶性肿瘤的发病相关,已成为近年来肿瘤学研究的新方向.OTUB1可以正向调节抑癌基因p53、细胞凋亡抑制蛋白(c-IAP)、转化生长因子-β(TGF-β)信号通路、鼠双微基因4(MDMX),负向调节雌激素受体α,从而影响肿瘤信号通路.近年来越来越多的研究发现,OTUB1与肿瘤的发生、发展和转移密切相关.本文就OTUB1在肿瘤中的研究进展作一综述.     

Association between FTO gene polymorphism and cancer risk: evidence from 16,277 cases and 31,153 controls

A recent genome-wide association study showed that the rs9939609 polymorphism in the fat mass and obesity-associated (FTO) gene was associated with body mass index (BMI)/obesity in Europeans. Subsequently, several studies have investigated the association between FTO polymorphism and cancer risk. However, the results have been inconsistent. In this study, a meta-analysis was performed to clarify the association between FTO polymorphism and cancer risk. Published literature from PubMed and Embase databases were retrieved. Pooled odds ratio (OR) with 95 % confidence interval (CI) was calculated using fixed-effects model. A total of 13 studies involving 16,277 cases and 31,153 controls were identified. The results suggested that FTO rs9939609 polymorphism was not significantly associated with the increased risk of cancer (OR = 1.01, 95 %CI 0.98-1.04), with the exception that a statistically significant association was found for pancreatic cancer (OR = 1.10, 95 %CI 1.03-1.19). No publication bias was detected (Begg's test: P = 0.760; Egger's test: P = 0.553). Our meta-analysis indicated that there was no association between FTO rs9939609 polymorphism and the increased risk of cancer, although this polymorphism was marginally associated with pancreatic cancer. However, the conclusion should be made with caution since most included studies did not take BMI/obesity into account.     

硬脂酰辅酶A去饱和酶1与恶性肿瘤的研究进展

由于耐药性的产生和化疗药物的毒副反应,恶性肿瘤的化疗效果一直不满意。为了寻找新的、选择性的抗肿瘤药物,人们对肿瘤细胞的代谢异常作了大量研究。越来越多的研究发现,肿瘤组织的恶性生物学行为与其特殊的物质代谢和能量代谢密切相关。增殖迅速的肿瘤细胞的一个代谢特点为脂质生成增多。硬脂酰辅酶A去饱和酶1（Stearoyl-coenzyme A desaturase 1,SCD1）是催化饱和脂肪酸向单不饱和脂肪酸转变的限速酶,与肥胖、脂肪性肝脏病变、胰岛素抵抗等一系列的代谢综合征及癌症的发生、发展密切相关。研究SCD1在恶性肿瘤中的作用将为肿瘤患者化疗提供新的治疗靶点。      

Estrogen induces endometrial cancer cell proliferation and invasion by regulating the fat mass and obesity-associated gene via PI3K/AKT and MAPK signaling pathways

Obesity is generally acknowledged as a risk factor for endometrial cancer, as accumulated adipocytes partly contribute to the increased production of estrogen which is involved in dysregulated cell growth and metastasis in early endometrial carcinogenesis. Thus we evaluated in this study expression of the fat mass and obesity-associated (FTO) gene in endometrial tumor tissues and further explored its role in β-estradiol (E2)-induced endometrial cancer cell proliferation and invasion. IHC staining showed that FTO overexpressed in endometrial carcinoma. Additionally, E2-induced FTO via activation of the PI3K/AKT and MPAK signal pathways contributed to enhanced proliferation and invasion. Therefore, this study provides a new insight on the mechanisms of E2-induced proliferation and invasion and the link between obesity and endometrial cancer, implying the possibility of using FTO as a potential therapeutic target for the treatment of endometrial cancer.     

FTO promotes the progression of cervical cancer by regulating the N6-methyladenosine modification of ZEB1 and Myc

Cervical cancer is a malignant tumor of the cervix in women. However, the pathogenesis of cervical cancer has not been fully understood. N6-methyladenosine (m6A) is a kind of RNA modification that plays a critical role in cancer development. We aim to find out the possible m6A regulatory mechanism of the fat mass and obesity-associated protein (FTO) on the development of cervical cancer. The proliferative capacity of cervical cancer cells was detected by 3-(4,5-dimethylthiazol-2-yl)−2,5-diphenyl-2H-tetrazolium bromide (MTT), colony formation and 5-ethynyl-20-deoxyuridine (EdU) staining. The migration and invasion of cervical cancer cells were determined by transwell assay. The function of FTO on tumor growth was evaluated by a xenograft model. We found that FTO was highly expressed in cervical cancer tissues and cell lines. FTO silencing suppressed the proliferation, migration, and invasion of cervical cancer cells. Mechanistically, FTO modulated the m6A modification of Zinc finger E-box binding homeobox 1 (ZEB1) and Myelocytomatosis oncogene (Myc). Furthermore, ZEB1 and Myc overexpression reverse the effect of FTO knockdown on the malignant behaviors of cervical cancer cells. FTO may be a novel therapeutic target for cervical cancer.     

脂类代谢与结直肠癌发生、发展关系的研究进展

脂类包括脂肪(甘油三酯)和类脂(磷脂、固醇类),提供机体必需脂肪酸和能量.脂类代谢紊乱被认为是包括结直肠癌在内的许多恶性肿瘤的代谢特征.脂类代谢异常会导致细胞膜结构变化、细胞信号传导异常、能量稳态失衡、基因表达和蛋白质分布破坏等分子变化,从而影响细胞增殖、分化、新陈代谢、凋亡以及信息传递等一系列细胞功能.高水平的脂肪酸...     

Lack of Association of the Fat Mass and Obesity Associated (FTO) Gene rs9939609 Polymorphism with Breast Cancer Risk: a Systematic Review and Meta-Analysis Based on Case - Control Studies

Background: Previously published data on any association of the fat mass and obesity-associated (FTO) gene with breast cancer risk remain inconclusive. Therefore, we conducted the present meta-analysis of links between breast cancer and the FTO rs9939609 polymorphism. Methods: We have conducted a systematic review of the English literature by searching PubMed, Google Scholar and ISI Web of Knowledge databases for studies on associations between the FTO rs9939609 polymorphism and breast cancer risk. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to estimate the strength of the association using fixed- or random-effects model. Results: We included five studies with 1134 cases and 1453 controls. Overall, no significant association between the FTO rs9939609 polymorphism and risk of breast cancer was found. On subgroup analysis by ethnicity, there was still no significant association detected. Conclusions: To our knowledge, this is the first meta-analysis of the FTO rs9939609 polymorphism and risk of breast cancer. However, the present meta-analysis suggested that only there might be a significant association of the CXCL12 rs1801157 polymorphisms with breast cancer risk.     

己糖激酶Ⅱ与肿瘤增殖及靶向治疗

肿瘤细胞所需能量主要来自有氧糖酵解途径,即Warburg效应,该生化过程同时为肿瘤细胞提供生长所需的大量前体物质.已糖激酶Ⅱ(HK-Ⅱ)为糖酵解的限速酶,在肿瘤组织中高表达,与肿瘤的能量代谢密切相关.近年来研究表明肿瘤细胞中的HK-Ⅱ不仅介导Warburg效应,还能抑制肿瘤细胞凋亡、调节自噬而发挥促进肿瘤增殖的作用.已在多种肿瘤细胞中证实,阻断HK-Ⅱ基因表达及应用HK-Ⅱ的小分子抑制剂均可起到杀伤肿瘤的作用,以HK-Ⅱ为靶点的抑制剂有可能成为新一代靶向药物.     

Lactate dehydrogenase A negatively regulated by miRNAs promotes aerobic glycolysis and is increased in colorectal cancer

Reprogramming metabolism of tumor cells is a hallmark of cancer. Lactate dehydrogenase A (LDHA) is frequently overexpressed in tumor cells. Previous studies has shown higher levels of LDHA is related with colorectal cancer (CRC), but its role in tumor maintenance and underlying molecular mechanisms has not been established. Here, we investigated miRNAs-induced changes in LDHA expression. We reported that colorectal cancer express higher levels of LDHA compared with adjacent normal tissue. Knockdown of LDHA resulted in decreased lactate and ATP production, and glucose uptake. Colorectal cancer cells with knockdown of LDHA had much slower growth rate than control cells. Furthermore, we found that miR-34a, miR-34c, miR-369-3p, miR-374a, and miR-4524a/b target LDHA and regulate glycolysis in cancer cells. There is a negative correlation between these miRNAs and LDHA expression in colorectal cancer tissues. More importantly, we identified a genetic loci newly associated with increased colorectal cancer progression, rs18407893 at 11p15.4 (in 3′-UTR of LDHA), which maps to the seed sequence recognized by miR-374a. Cancer cells overexpressed miR-374a has decreased levels of LDHA compared with miR-374a-MUT (rs18407893 at 11p15.4). Taken together, these novel findings provide more therapeutic approaches to the Warburg effect and therapeutic targets of cancer energy metabolism.