Super enhancer inhibitors suppress MYC driven transcriptional amplification and tumor progression in osteosarcoma

Osteosarcoma is the most common primary bone sarcoma that mostly occurs in young adults. The causes of osteosarcoma are heterogeneous and still not fully understood. Identification of novel, important oncogenic factors in osteosarcoma and development of better, effective therapeutic approaches are in urgent need for better treatment of osteosarcoma patients. In this study, we uncovered that the oncogene MYC is significantly upregulated in metastastic osteosarcoma samples. In addition, high MYC expression is associated with poor survival of osteosarcoma patients. Analysis of MYC targets in osteosarcoma revealed that most of the osteosarcoma super enhancer genes are bound by MYC. Treatment of osteosarcoma cells with super enhancer inhibitors THZ1 and JQ1 effectively suppresses the proliferation, migration, and invasion of osteosarcoma cells. Mechanistically,THZ1 treatment suppresses a large group of super enhancer containing MYC target genes including CDK6 and TGFB2. These findings revealed that the MYC-driven super enhancer signaling is crucial for the osteosarcoma tumorigenesis and targeting the MYC/super enhancer axis represents as a promising therapeutic strategy for treatment of osteosarcoma patients.

N-myc downstream regulated gene 1 inhibition of tumor progression in Caco2 cells

BACKGROUND Invasion and migration are the irreversible stages of colorectal cancer(CRC).The key is to find a sensitive,reliable molecular marker that can predict the migration of CRC at an early stage.N-myc downstream regulated gene 1(NDRG1)is a multifunctional gene that has been tentatively reported to have a strong relationship with tumor invasion and migration,however the current molecular role of NDRG1 in CRC remains unknown.AIM To explore the role of NDRG1 in the development of CRC.METHODS NDRG1 stably over-expressed Caco2 cell line was established by lentiviral infection and NDRG1 knock-out Caco2 cell line was established by CRISPR/Cas9.Furthermore,the mRNA and protein levels of NDRG1 in Caco2 cells after NDRG1 over-expression and knockout were detected by real-time polymerase chain reaction and western blot.The cell proliferation rate was measured by the cell counting kit-8 method;cell cycle and apoptosis were detected by flow cytometry;invasion and migration ability were detected by the 24-transwell method.RESULTS NDRG1 over-expression inhibited Caco2 proliferation and the cell cycle could be arrested at the G1/S phase when NDRG1 was over-expressed,while the number of cells in the G2 phase was significantly increased when NDRG1 was knocked out.This suggests that NDRG1 inhibited the proliferation of Caco2 cells by arresting the cell cycle in the G1/S phase.Our data also demonstrated that NDRG1 promotes early cell apoptosis.Invasion and migration of cells were extensively inhibited when NDRG1 was over-expressed.CONCLUSION NDRG1 inhibits tumor progression in Caco2 cells which may represent a potential novel therapeutic strategy for the treatment of CRC.

HGF/SF-Met signaling in tumor progression

Tumor progression is a multi-step process that requires a sequential selection of specific malignant phenotypes. Met activation may induce different phenotypes depending on tumor stage: inducing proliferation and angiogenesis in pri- mary tumors, stimulating motility to form micrometastases, and regaining the proliferation phenotype to form overt metastases. To study how HGF/SF-induced proliferative phenotypes switch to the invasive phenotype is important for understanding the mechanism of tumor progression and will provide an attractive target for cancer intervention and therapy.

Rate of local tumor progression following radiofrequency ablation of pathologically early hepatocellular carcinoma

AIM To evaluate whether pathologically early hepatocellular carcinoma(HCC) exhibited local tumor progression after radiofrequency ablation(RFA) less often than typical HCC.METHODS Fifty pathologically early HCCs [tumor diameter(mm): mean, 15.8; range, 10-23; follow-up days after RFA: median, 1213; range, 216-2137] and 187 typical HCCs [tumor diameter(mm): mean, 15.6; range, 6-30; follow-up days after RFA: median, 1116; range, 190-2328] were enrolled in this retrospective study. The presence of stromal invasion(namely, tumor cell invasion into the intratumoral portal tracts) was considered to be the most important pathologic finding for the diagnosis of early HCCs. Typical HCC was defined as the presence of a hyper-vascular lesion accompanied by delayed washout using contrastenhanced computed tomography or contrast-enhanced magnetic resonance imaging. Follow-up examinations were performed at 3-mo intervals to monitor for signs of local tumor progression. The local tumor progression rates of pathologically early HCCs and typical HCCs were then determined using the Kaplan-Meier method.RESULTS During the follow-up period for the 50 pathologically early HCCs, 49(98%) of the nodules did not exhibit local tumor progression. However, 1 nodule(2%) was associated with a local tumor progression found 636 d after RFA. For the 187 typical HCCs, 46(24.6%) of the nodules exhibited local recurrence after RFA. The follow-up period until the local tumor progression of typical HCC was a median of 605 d, ranging from 181 to 1741 d. Among the cases with typical HCCs, local tumor progression had occurred in 7.0%(7/187), 16.0%(30/187), 21.9%(41/187) and 24.6%(46/187) of the cases at 1, 2, 3 and 4 years, respectively. Pathologically early HCC was statistically associated with a lower rate of local tumor progression, compared with typical HCC, when evaluated using a log-rank test(P = 0.002). CONCLUSION The rate of local tumor progression for pathologically early HCCs after RFA was significantly lower than that for typical HCCs.

Thymoquinone Suppresses Cellular Proliferation, Inhibits VEGF Production and Obstructs Tumor Progression and Invasion in the Rat Model of DMH-Induced Colon Carcinogenesis

A myriad of medicinal effects has been attributed to Thymoquinone (TQ), the major biological-active component of Nigella sativa. TQ has been shown to exhibit potent anti-tumor activities. The present work was undertaken to further explore TQ’s chemopreventive efficacy against 1, 2-dimethylhydrazine (DMH)-induced colon carcinogenesis in the rat model through a two-phase study (initiation and post-initiation) and to evaluate its potential impact on tumor progression and invasion in vivo. TQ treatment in the initiation phase significantly reduced tumor incidence, multiplicity and mean tumor volume. However, although mean tumor volume and multiplicity were decreased upon TQ treatment in the post-initiation phase, TQ did not reduce incidence significantly. Cellular proliferation, as assessed by expression of colonic PCNA, was shown to be inhibited in consequence to TQ treatment in both phases, with a more pronounced reduction in the initiation phase. In addition, our results demonstrated an appreciable negative impact of TQ on vascular endothelial growth factor (VEGF) production in tumor-bearing rats. Furthermore, we provided evidence that TQ-treatment, in both phases, tended to considerably suppress tumor progression and invasion. Taken together, the present study demonstrated that TQ, at an orally daily dose of 10 mg/kg, has a chemopreventive effect in the initiation phase, and has the potential to attenuate tumor burden, suppress progression of pre-neoplastic lesions and to inhibit tumor growth in the post-initiation phase of DMH-induced colon carcinogenesis, We surmise that such effects of TQ may be due to suppression of cellular proliferation and inhibition of VEGF production. The results could provide an effective chemopreventive approach in the primary prevention of colon cancer in humans in the next future, and illuminate a promising horizon to combat progression of benign colonic pre-neoplastic lesions into malignant metastatic tumors and to manage colon cancer.

Ferroptosis:a critical mechanism of N^(6)-methyladenosine modification involved in carcinogenesis and tumor progression

Ferroptosis is an iron-dependent regulatory cell necrosis induced by iron overload and lipid peroxidation.It occurs when multiple redoxactive enzymes are ectopically expressed or show abnormal function.Hence,the precise regulation of ferroptosis-related molecules is mediated across multiple levels,including transcriptional,posttranscriptional,translational,and epigenetic levels.N^(6)-methyladenosine(m^(6)A)is a highly evolutionarily conserved epigenetic modification in mammals.The m^(6)A modification is commonly linked to tumor proliferation,progression,and therapy resistance because it is involved in RNA metabolic processes.Intriguingly,accumulating evidence suggests that dysregulated ferroptosis caused by the m^(6)A modification drives tumor development.In this review,we summarized the roles of m^(6)A regulators in ferroptosis-mediated malignant tumor progression and outlined the m^(6)A regulatory mechanism involved in ferroptosis pathways.We also analyzed the potential value and application strategies of targeting m^(6)A/ferroptosis pathway in the clinical diagnosis and therapy of tumors.

The role and research progress of MDSC in immune aging-related diseases

Myeloid-derived suppressor cells(MDSCs)are a group of heterogeneous immature cells with a strong immunosuppressive function in myeloid cells,which are impeded in the differentiation of myeloid cells under the pathological conditions of hypoxia,inflammation,infection,and cancer.As individuals age,there is a significant increase in myeloid-derived suppressor cells(MDSCs),which subsequently enhance the immunosuppressive functions of Tregs(regulatory T cells)and Bregs(regulatory B cells).Therefore,MDSC may be related to immune system remodeling,thereby preventing excessive lesions caused by aging.This indicates that MDSC could serve as a potent inducer of immune senescence.Immune senescence,characterized by immune dysfunction with aging,is closely linked to the onset of diseases like infections,pulmonary fibrosis,and tumors.To achieve the purpose of anti-aging by intervening in immune aging and slow down the occurrence and development of related diseases.Therefore,understanding the biological characteristics of MDSC and its role in immune aging is crucial for immunotherapy targeting MDSC.This article reviews the different roles of MDSC in immune aging and its relationship with pulmonary fibrosis,tumor and other related diseases to provide theoretical basis for more comprehensive targeted MDSC immunotherapy.

The Dual Effects of Interleukin-18 in Tumor Progression

Interleukin-18 （IL-18） was discovered as an interferon-y-inducing factor and had a critical role in inflammatory and immune respouse. It stimulates natural killer （NK） and T cells and enhances Thl immune response. These activated immune cells eliminate cancer cells and virus-infected cells effectively. However, IL-18 has also been found to promote tumor progression. Higher expression or secretion level of IL-18 is detected in various cancer cells in comparison with normal control, and IL-18 is able to induce angiogenesis, migration/metastasis, proliferation and immune escape. These dual effects and the mechanism of IL-18 need to be investigated further as it relates to cancer.

RNA editingof SLC22A3 causes early tumor progression in familial esophageal cancer patients

Subject Code:H16With the support by the National Natural Science Foundation of China,a collaborative study by the Research groups led by Prof.Fu Li(付利)from the Cancer Research Center,Shenzhen University School of Medicine and Prof.Guan Xinyuan(关新元)from the University of Hong Kong reported that an

Research Progress on the Role of miRNA-448 in Tumor

MicroRNA (miRNA) is a class of endogenous non-coding and regulatory single stranded small RNA molecules, about 18 - 24 nucleotides in length. More than 800 miRNA coding genes have been identified in the human genome, and about 113 target genes are predicted to be regulated, which distinguishes it from most oligonucleotides and functional RNA degraded fragments. It is involved in the regulation of cell proliferation, differentiation, apoptosis and other cell activities. At the same time, it is abnormal in liver cancer, breast cancer, glioma and other tumors, becoming a new biomarker, and participating in cancer differentiation, invasion and metastasis through the interaction with multiple target genes, such as SATB1, NF-KB and 5-HT2B. Mir-448 is abnormally expressed in a variety of tumor cells, such as liver cancer and non-small cell lung cancer. mirNA-448 may play a very important role in tumors. In order to deepen the understanding of the role of mirNA-448 in tumors, this paper reviews the research progress of the role of mirNA-448 in tumors.

单次灌注化疗后膀胱持续生理盐水冲洗或增加中低风险非肌层浸润性膀胱癌进展风险

目的探究行经尿道膀胱肿瘤切除术(TURBT)的中低风险非肌层浸润性膀胱癌(NMIBC)患者单次即刻膀胱灌注化疗(SIIC)后膀胱持续生理盐水冲洗(CSBI)的治疗效果。方法回顾性分析2004年1月—2019年12月于北京大学人民医院泌尿外科行TURBT的211例中低风险NMIBC患者的临床资料,根据患者SIIC后是否进行CSBI分为CSBI组和无CSBI组,比较两组患者的复发率、进展率、无复发生存率和无进展生存率。通过Cox单因素及多因素回归分析探究CSBI是否为患者肿瘤复发和进展的危险因素。结果两组患者的基线资料、复发率和进展率比较,差异均无统计学意义(P>0.05)。两组患者无复发生存率比较无明显差异,而CSBI组无进展生存率更低(χ^(2)=8.270,P=0.004)。在多因素Cox回归分析中,糖尿病(HR:2.240,95%CI:1.066~4.704,P=0.033)和多发肿瘤(HR:3.060,95%CI:1.639~5.711,P<0.001)是中低风险NMIBC患者肿瘤复发的独立危险因素,CSBI(HR:7.914,95%CI:1.710~36.632,P=0.008)是肿瘤进展的独立危险因素。结论SIIC后CSBI可能会增加中低风险NMIBC患者的进展风险,但该结论仍需要更大样本量进行验证。

TPL2抑制剂对溃疡性结肠炎小鼠的作用及机制研究

目的探讨抑制肿瘤进展位点2(tumor progression locus 2,TPL2)/细胞外信号调节激酶1/2(extracellular signal-regulated kinase1/2,ERK1/2)信号通路对实验性溃疡性结肠炎(ulcerative colitis,UC)小鼠肠道损伤和炎症的保护作用。方法将30只C57BL/6J小鼠分为正常对照组、模型对照组、高剂量TPL2抑制剂组、低剂量TPL2抑制剂组、美沙拉嗪组,每组6只。比较各组小鼠疾病活动指数(disease activity index,DAI)和组织学损伤评估(histological index,HI)评分,采用实时定量PCR检测结肠中IL-6、TNF-α、TPL2和ERK1/2 mRNA表达水平,Western blotting检测结肠中TPL2、ERK1/2蛋白表达水平。结果与正常对照组相比较,模型对照组小鼠的DAI、HI评分均升高,结肠中IL-6、TNF-α、TPL2、ERK1/2 mRNA和蛋白表达均增加(均P<0.05)。与模型对照组相比较,给予TPL2抑制剂干预的两组小鼠DAI、HI评分均降低,结肠中IL-6、TNF-αmRNA相对表达量降低,结肠中TPL2、ERK1/2 mRNA和蛋白表达均下降(均P<0.05)。结论TPL2抑制剂可以改善UC小鼠肠道组织损伤与炎症,其分子机制与抑制其下游ERK1/2信号通路相关。

HN1L、PLK1在食管胃交界腺癌中的表达及与肿瘤进展和患者预后的关系研究

目的探讨血液和神经表达1样蛋白(HN1L)、Polo样激酶1蛋白(PLK1)在食管胃交界腺癌(AEGJ)中的表达及其与肿瘤进展和患者预后的关系。方法回顾性收集2017年6月至2020年6月邯郸市第一医院手术切除的105例AEGJ组织及其距离肿瘤边缘5 cm处的癌旁组织。采用免疫组化法观察并比较癌组织和癌旁组织HN1L、PLK1表达评分,比较不同临床特征AEGJ患者癌组织HN1L、PLK1表达评分,采用Pearson相关分析两种蛋白表达评分的相关性,根据表达评分分组,生存分析采用Kaplan-Meier生存曲线,预后分析采用多因素Cox回归分析。结果癌组织中HN1L、PLK1表达评分均显著高于癌旁组织(均P<0.05)。相比于肿瘤-淋巴结-远处转移(TNM)分期Ⅰ~Ⅱ期、无淋巴结转移AEGJ患者,TNM分期Ⅲ~Ⅳ期、有淋巴结转移AEGJ患者癌组织HN1L、PLK1表达评分显著升高(均P<0.05)。癌组织HN1L表达评分与PLK1表达评分呈正相关(P<0.01)。AEGJ患者3年总生存率为43.8%。生存分析显示,HN1L高表达组患者和PLK1高表达组患者3年总生存率均显著低于HN1L低表达组和PLK1低表达组(均P<0.01)。多因素Cox回归分析显示,淋巴结转移、TNM分期Ⅲ~Ⅳ期、HN1L和PLK1高表达是影响AEGJ患者预后的独立危险因素(均P<0.01)。结论AEGJ患者癌组织HN1L、PLK1表达与肿瘤恶性程度有关,可作为预测患者预后的潜在指标。

麦冬抗肿瘤作用机制研究进展

麦冬是我国的传统中药,具有养阴生津、润肺清心的功效。越来越多的研究发现,麦冬除了传统功效外还具有对多种肿瘤的抑制作用。麦冬可通过抑制肿瘤细胞增殖、诱导肿瘤细胞凋亡、坏死性凋亡、铁死亡、焦亡、自噬、细胞周期阻滞、抑制肿瘤细胞转移和血管生成以及逆转肿瘤细胞耐药性等多种机制发挥抗肿瘤作用。对近年来麦冬块根提取物及其活性单体的抗肿瘤作用研究进展进行综述,为麦冬抗肿瘤的深入研究和对麦冬的进一步开发利用提供可借鉴的思路和方向。

细胞衰老与肿瘤相关研究进展

衰老是一种持久的、不可逆的生长停滞状态,往往伴随着形态结构的改变、功能的减退以及衰老相关表型的分泌。近年来,越来越多的研究证实细胞衰老与肿瘤进展密切相关。本文就细胞衰老与肿瘤的关系,以及通过调控衰老治疗肿瘤的相关研究进展进行综述。

半枝莲抗肿瘤的信号通路研究进展

半枝莲在中国药用历史悠久,经现代研究证实含有黄酮类、多糖类、二萜类等多种抗肿瘤有效成分。梳理近年来半枝莲及其活性成分靶向肿瘤的各个信号通路的相关文献发现,半枝莲及其活性成分通过调控磷脂酰肌醇3-激酶/蛋白激酶B(PI3K/Akt)、酪氨酸蛋白激酶/信号转导和转录激活因子(JAK/STAT)、Wnt/β-连环蛋白(Wnt/β-cate-nin)、丝裂原活化蛋白激酶(MAPK)、半胱氨酸蛋白酶(Caspase)途径、核因子-κB(NF-κB)、蛋白53(p53)和Hedgehog等多条信号通路,发挥抑制肿瘤细胞增殖、诱导肿瘤细胞凋亡、降低迁移和侵袭能力、抗肿瘤血管形成、调节机体的免疫功能等作用,达到抗肿瘤效应。广泛应用于结肠癌、肺癌、肝癌、乳腺癌等多种肿瘤疾病的治疗。研究以细胞信号通路为切入点,总结半枝莲抗肿瘤的作用机制,以期为深入挖掘半枝莲抗肿瘤机制及其临床应用提供参考。

人表皮因子受体-2在膀胱尿路上皮癌和上尿路上皮癌中表达的差异性分析

目的探索人表皮因子受体-2(HER-2)在膀胱尿路上皮癌(UBC)和上尿路上皮癌(UTUC)中表达的差异性,及其与这两种疾病复发及进展的相关性。方法回顾性分析2015年11月—2022年6月兰州大学第二医院泌尿外科收治的184例尿路上皮癌患者,按照肿瘤部位分为UBC组及UTUC组,比较两组中HER-2的阳性表达率,绘制生存曲线。比较两组患者的无复发生存期(RFS)及无进展生存期(PFS)。应用Cox比例风险模型分析HER-2阳性表达对UBC及UTUC患者复发及进展的影响。结果UBC患者HER-2阳性表达显著高于UTUC患者(49.6%vs.32.2%,P=0.027)。UTUC患者中,肾盂癌患者HER-2阳性表达相较于输尿管癌差异无统计学意义(30.6%vs.34.8%,P>0.05)。Cox多因素回归分析显示HER-2阳性表达影响UBC复发(P<0.001);HER-2阳性表达(P<0.001)、肿瘤直径≥3 cm(P<0.001)、分期≥T2(P=0.003)以及多发肿瘤灶(P=0.033)均可影响UBC进展;HER-2阳性表达对UTUC复发及进展的影响差异无统计学意义。结论UBC组患者HER-2的阳性表达显著高于UTUC,HER-2阳性表达可能提示UBC复发及进展的风险增加,而对UTUC的复发及进展则无明显影响。因此不建议以HER-2表达来独立预测UTUC的复发及进展风险。

细胞焦亡及其在肿瘤放疗中的作用机制研究进展

细胞焦亡是一种新型细胞死亡方式,在肿瘤研究中具有双向调节作用,一方面,诱导细胞焦亡促进癌细胞死亡,抑制肿瘤细胞增殖,增强放化疗敏感性、改善抗肿瘤免疫;另一方面,放射治疗是恶性肿瘤治疗的重要手段,焦亡诱发放射性炎症损伤,影响放疗疗效,但细胞焦亡在放疗中的潜在作用机制尚未完全阐明。本文通过概述细胞焦亡在抗肿瘤治疗中的作用机制以及细胞焦亡在放疗中的双重作用,并对细胞焦亡在放疗中的应用及困境进行展望,探讨靶向细胞焦亡提高放疗疗效及减轻放射性损伤的可行性,期望为放疗后续作用机制研究提供参考,为放疗靶向焦亡研究提供新方向。

小檗碱抗胃癌的药理作用及其机制研究进展

胃癌的发病率和死亡率在我国各种恶性肿瘤中均位居第三,是威胁人民生命健康的重要杀手。小檗碱除具有抗炎、抗感染、调节心血管等作用外,对肝癌、结直肠癌、脑瘤、头颈部肿瘤、泌尿系肿瘤等也有较好的作用,因而可能是一个潜在的抗肿瘤药物。该文主要从小檗碱预防胃癌的发生,以及对SGC7901、BGC-823、MKN-45等人胃癌细胞的抑制和诱导凋亡等方面进行了综述,以期为小檗碱的进一步临床开发提供参考。

长链非编码RNA Linc00467在肿瘤中的作用研究进展

长链非编码RNA(lncRNA)是一类转录本长度大于200 nt的不编码蛋白质的RNA分子,其在肿瘤发展过程中的作用目前正被广泛研究。lncRNA Linc00467是一种新发现的lncRNA,且已被证实在肝癌、胃癌、肺癌、结直肠癌等多种肿瘤中均有异常表达。其可调节肿瘤细胞的恶性进程,并影响患者的生存及预后,是与多种恶性肿瘤相关的癌基因。笔者结合目前已有报道,对Linc00467在恶性肿瘤中的作用及其机制研究进展作一综述,以期为Linc00467更全面的研究提供帮助。