复方苦参注射液联合化疗对人胰腺癌的抑制作用

目的:探索复方苦参注射液对人胰腺癌细胞SW1990的体外直接抑制作用,以及不同浓度的苦参注射液与化疗联合应用时的协同作用。方法:采用MTT法检测不同浓度的复方苦参注射液以及复方苦参注射液与化疗药联合应用对人胰腺癌细胞SW1990的体外抑制率。结果:不同浓度的复方苦参注射液均对人胰腺癌细胞SW1990有抑制作用,其抑制作用与浓度成正相关,不同浓度的苦参注射液与化疗药联用对人胰腺癌细胞SW1990的体外抑制作用均明显高于单用化疗药。结论:复方苦参注射液对人胰腺癌细胞SW1990有体外直接抑制作用,该药联合化疗有协同抗肿瘤作用。     

冬凌草甲素通过下调XIAP增强吉西他滨对胰腺癌SW1990的抑制作用

【摘要】目的探讨冬凌草甲素在体外联合吉西他滨对胰腺癌细胞株SW1990抑制作用及其可能机制。方法 不同浓度的冬凌草甲素（0、10、20、40、80、160μmol/L）作用胰腺癌SW1990细胞24、48、72h后,CCK-8法检测胰腺癌细胞株SW1990细胞的增殖作用;冬凌草甲素（40μmol/L）与吉西他滨（20μmol/L）单独及联合处理细胞48h,并设立对照组, CCK-8法检测SW1990细胞的存活率;Annexin V-FITC/PI双染流式细胞术检测细胞凋亡情况;RTPCR检测SW1990细胞中NF-κB和XIAP基因的表达水平。结果冬凌草甲素对胰腺癌SW1990细胞的增殖抑制作用呈明显的剂量与时间依赖性;与其他各组相比,冬凌草甲素联合吉西他滨组细胞存活率明显降低（P<0.05）,凋亡率显著升高（P<0.05）;另外,联合组明显下调胰腺癌细胞中NF-κB和XIAP表达水平（P<0.05）。结论冬凌草甲素在体外能显著增强吉西他滨对胰腺癌SW1990细胞的抗瘤效果,其机制可能是通过下调NF-κB及其下游XIAP 的表达,进而诱导胰腺癌细胞的凋亡而实现.     

Role of nuclear factor-kappaB on emodin-induced sensitization of pancreatic cancer to gemcitabine

In view of gemcitabine resistance has limited clinical activity of gemcitabine as a cellulotoxic drug in pancreatic cancer patients, this study is designed to investigate the effect of emodin on the sensitivity of pancreatic cancer to gemcitabine as well as its mechanism. After gemcitabine-resistant pancreatic cancer cell line (SW1990/GZ) was established by escalating doses of gemcitabine serially in pancreatic cancer cell line (SW1990). The cellular proliferation was detected by cell counting kit-8 (CCK-8) assay. Flow cytometry (FCM) was used to determine apoptosis of pancreatic cancer cells. The activity of NF-kappaB in pancreatic cancer cells was measured by electrophoretic mobility shift assay (EMSA). Western blotting was used to detect the protein expression of Bcl-2 and Survivin in SW1990/GZ cells. Metastatic model simulating human pancreatic cancer was established by orthotopic implantation of histologically intact human tumor tissue into pancreatic wall of nude mice. Also, immunohistochemistry was used to detect the positive expression of Ki-67, NF-kappaB, Bcl-2 and Survivin in the tumors. The results show that pretreatment of cells with emodin followed by gemcitabine induced a higher percentage of growth inhibition and apoptosis of pancreatic cancer cells than that of gemcitabine alone. In addition to in vitro results, emodin in combination with gemcitabine is much more effective as an antitumor agent compared to either agent alone in the orthotopic tumor model. Further study showed that the emodin with or without gemcitabine significantly down-regulates NF-kappaB and its regulated molecules such as Bcl-2 and Survivin proteins both in vitro and in vivo. It is concluded that inactivation of NF-kappaB signaling pathway by emodin resulting in the chemosensitization of pancreatic cancer to gemcitabine, which is likely to be an important and novel strategy for the treatment of pancreatic cancer.     

NF-κB在大黄素增强胰腺癌吉西他滨化疗敏感性中的作用

为探讨大黄素增强胰腺癌吉西他滨化疗敏感性的作用及其机制,本研究诱导建立耐100 nmol·L-1吉西他滨的人胰腺癌SW1990细胞株(SW1990/GZ),在体外实验中,应用CCK-8法检测细胞增殖活性;流式细胞术检测细胞凋亡;凝胶电泳迁移率实验(EMSA)检测细胞中NF-κB活性;Western blotting检测细胞中蛋白表达水平;在体内实验中,建立裸鼠胰腺癌原位移植模型;免疫组织化学法检测肿瘤组织中蛋白表达。结果表明,大黄素预处理可显著增强吉西他滨对胰腺癌细胞的生长抑制和诱导凋亡作用;大黄素联合吉西他滨可显著抑制胰腺癌原位移植瘤生长;大黄素还可下调体内外胰腺癌中NF-κB及其调控蛋白Bcl-2和Survivin的表达。提示NF-κB在大黄素增敏胰腺癌吉西他滨化疗中具有重要意义。     

5-FC诱导胞嘧啶脱氨酶基因修饰的胰腺癌细胞凋亡的研究(英文)

目的:探讨5-氟胞嘧啶(5-FC)对CD基因修饰的胰腺癌细胞凋亡的影响及特征。方法:以腺病毒介导的CD基因转染胰腺癌SW1990细胞,以Western blot检测基因蛋白表达,通过细胞形态学、DNA凝胶电泳和流式细胞术观察5-FC对表达CD基因的SW1990细胞凋亡的影响作用。结果:以含CD基因的重组腺病毒转染的SW1990细胞,给予5-FC(100μmol·L~(-1)),培养48h,细胞出现典型的凋亡形态、DNA梯带改变及凋亡峰,细胞在G_1、S和G_2/M各期分别为64％、11％和7％,凋亡率达34.6％。结论:5-FC的上述诱导凋亡作用可能是胰腺癌CD基因疗法的重要机制。     

HSV-TK/GCV自杀基因系统对人胰腺癌细胞的作用

目的 运用自杀基因系统HSV-TK／GCV治疗人胰腺癌细胞SW1990的实验研究，并证实旁观效应。方法 通过脂质体介导的基因转移方法将含有单纯疱疹病毒胸苷激酶基因(her—pessimplex virus thymidine kinase gene，HSV-TK)的复制缺陷型逆转录病毒载体GINaTK导入包装细胞PA317，然后利用细胞产生的假病毒颗粒感染人胰腺癌细胞系SW1990细胞。在SW1990／TK细胞培养物中加入抗病毒前药GCV，观察GCV对该细胞的杀伤作用及旁观效应。结果 实验表明GCV对SW1990／TK有显的抑制及杀灭作用，同时表现出强烈的旁观效应。结论 HSV-TK／C-CV自杀基因系统对胰腺癌细胞有生长抑制及杀伤作用，为临床应用提供了实验依据。     

雷公藤内酯醇降调胰腺癌细胞5-脂氧合酶表达作用研究

目的探讨雷公藤内酯醇（TL）对胰腺癌细胞中5 脂氧合酶(5 LOX)蛋白表达及胰腺癌细胞凋亡的影响。方法应用RT PCR法和免疫细胞化学法检测胰腺癌细胞株SW1990中5 LOX表达，同时应用流式细胞术检测胰腺癌细胞SW1990的凋亡指数。结果胰腺癌细胞株SW1990表达5 LOX，正常胰腺组织不表达； TL可抑制SW1990中5 LOX表达，并促进胰腺癌细胞SW1990凋亡，作用随浓度的增加而增强(P＜0.01)；细胞凋亡与5 LOX蛋白的表达相关(P＜0.01)。结论TL可抑制胰腺癌细胞SW1990中5 LOX的表达，并促进胰腺癌细胞凋亡     

Development of a combination drug-eluting bead: towards enhanced efficacy for locoregional tumour therapies

Drug-eluting beads (DEBs) are becoming a mainstay locoregional therapy for hepatic malignancies but are currently loaded with single drugs alone. Here, we wished to prepare DEB containing different drug combinations, to screen their efficacy using an in-vitro cell culture assay and to include any promising combinations that demonstrate additive efficacy in an in-vivo model of locoregional tumour treatment. A modified in-vitro assay was used based upon the use of 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) with either HepG2 liver cancer or PSN1 pancreatic cancer cell lines. The comparative cytotoxicity of DEB combinations prepared containing doxorubicin, irinotecan, topotecan and rapamycin was evaluated. Those combinations that demonstrated an additive cytotoxicity effect were investigated in vivo using a nude mouse xenograft model of pancreatic cancer. Although many of the DEB combinations showed either no effect or a slight antagonistic effect, the combination of doxorubicin and rapamycin DEBs demonstrated synergistic activity. On the basis of these findings, a method was developed to prepare a doxorubicin/rapamycin dual-loaded DEB, which was shown to possess the same drug-loading capacities, drug elution properties and HepG2 cell cytotoxicity synergy as the single drug-loaded DEB combination. Evaluation of this dual-loaded combination DEB versus the respective single drug-loaded DEBs in a mouse xenograft model of pancreatic cancer showed an equivalent tumour volume reduction as the doxorubicin DEB, but with less toxicity than the rapamycin DEB. The doxorubicin/rapamycin combination DEB offers great potential for enhanced efficacy in the locoregional treatment of malignant tumours.     

A binuclear complex constituted by diethyldithiocarbamate and copper(I) functions as a proteasome activity inhibitor in pancreatic cancer cultures and xenografts

It is a therapeutic strategy for cancers including pancreatic to inhibit proteasome activity. Disulfiram (DSF) may bind copper (Cu) to form a DSF–Cu complex. DSF–Cu is capable of inducing apoptosis in cancer cells by inhibiting proteasome activity. DSF is rapidly converted to diethyldithiocarbamate (DDTC) within bodies. Copper(II) absorbed by bodies is reduced to copper(I) when it enters cells. We found that DDTC and copper(I) could form a binuclear complex which might be entitled DDTC–Cu(I), and it had been synthesized by us in the laboratory. This study is to investigate the anticancer potential of this complex on pancreatic cancer and the possible mechanism. Pancreatic cancer cell lines, SW1990, PANC-1 and BXPC-3 were used for in vitro assays. Female athymic nude mice grown SW1990 xenografts were used as animal models. Cell counting kit-8 (cck-8) assay and flow cytometry were used for analyzing apoptosis in cells. A 20S proteasome assay kit was used in proteasome activity analysis. Western blot (WB) and immunohistochemistry (IHC) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays were used in tumor sample analysis. The results suggest that DDTC–Cu(I) inhibit pancreatic cancer cell proliferation and proteasome activity in vitro and in vivo. Accumulation of ubiquitinated proteins, and increased p27 as well as decreased NF-κB expression were detected in tumor tissues of DDTC–Cu(I)-treated group. Our data indicates that DDTC–Cu(I) is an effective proteasome activity inhibitor with the potential to be explored as a drug for pancreatic cancer.     

Compound C17 inhibits the lung metastasis of breast cancer

Breast cancer is the most common cancer in females with extremely high lethality mainly due to the occurrence of metastasis, which is closely related to cancer stem-like cells (CSCs). It has been reported that CSC frequency in drug-resistant breast cancer and non-small cell lung cancer is reduced by activating dopamine D1 receptor (D1DR). In the present study, we aimed to investigate the effect of a compound C17 that can be used orally for breast cancer metastasis as well as the underlying mechanism involving the activation of D1DR. The confocal immunofluorescence analysis demonstrated that D1DR was up-regulated by C17. The cell survival and colony formation were inhibited by C17 through the detection by Sulforhodamine B colorimetric (SRB) assay and colony formation assay, respectively. Results from both wound healing assay and transwell assay demonstrated that C17 inhibited the migration of 4T1 cells. Flow cytometry analysis indicated that C17 significantly reduced the CSC frequency. In addition, C17 could inhibit the lung metastasis in 4T1 orthotopic mouse model of breast cancer without obvioustoxicity, and it could up-regulate the expression of intratumoral E-cadherin and down-regulate the expressions of Snail and N-cadherin in primary breast tumor, which might be related to the activation of D1DR. Our findings provided a potential candidate compound for the treatment of metastatic breast cancer with good compliance and safety.     

Antiangiogenic and antitumor activity of LP-261, a novel oral tubulin binding agent, alone and in combination with bevacizumab

LP-261 is a novel tubulin targeting anticancer agent that binds at the colchicine site on tubulin, inducing G2/M arrest. Screening in the NCI60 cancer cell lines resulted in a mean GI50 of approximately 100 nM. Here, we report the results of testing in multiple mouse xenograft models and angiogenesis assays, along with bioavailability studies. To determine the antiangiogenic activity of LP-261, both in vitro and ex vivo experiments were performed. Human Umbilical Vein Endothelial cells (HUVECs) were incubated with LP-261 at 50 nM to 10 μM. LP-261 was also tested in a rat aortic ring assay, from 20 nM to 10 μM. Multiple mouse xenograft studies were performed to assess in vivo antitumor activity. LP-261 was tested as a single agent in colon adenocarcinoma (SW620) and prostate cancer (LNCaP and PC3) xenografts, evaluating several different dosing schedules. LP-261 was also used in combination with bevacizumab in the SW620 xenograft model. LP-261 also exhibited high oral bioavailability and apparent lack of efflux by intestinal transporters such as ABCB1. LP-261 is a very potent inhibitor of angiogenesis, preventing microvessel outgrowth in the rat aortic ring assay and HUVEC cell proliferation at nanomolar concentrations. Complete inhibition of tumor growth was achieved in the PC3 xenograft model and shown to be schedule dependent. Excellent inhibition of tumor growth in the SW620 model was observed, comparable with paclitaxel. Combining oral, low dose LP-261 with bevacizumab led to significantly improved tumor inhibition. Oral LP-261 is very effective at inhibiting tumor growth in multiple mouse xenograft models and is well tolerated.     

Amy-2启动子的克隆和活性鉴定

目的 探讨人胰腺淀粉酶基因2(Amy-2)启动子在人胰腺组织特异性并验证其在胰腺细胞内的活性.方法 运用荧光素酶报告载体构建胰腺组织特异性启动子Amy-2质粒,将其转染人胰腺癌细胞系SWl990、PANc-1、正常人胰腺导管上皮细胞(HPDE)、乳腺癌(MCF-7)、肺癌(A549),验证其在胰腺细胞内的活性和特异性.利用分子生物学技术,结合PBS185载体构建载体pAmy2-Cre;在运用基因转染方法 将pAmy2-Cre的转染人胰腺癌细胞株Pane-1、BxPC-3,通过PCR、Western blot方法 观察pAmy-2的组织特异性.结果 成功构建pAmy-2-1uc和pAmy-2-Cre载体,证明了Amy-2的启动子在相应细胞内的转录活性;Amy-2的启动子能很好的驱动Cre蛋白表达.结论 Amy-2有较好的胰腺组织特异性和转录.     

Triphendiol (NV-196), development of a novel therapy for pancreatic cancer

Despite incremental progress in the treatment of pancreatic adenocarcinoma, the prognosis of patients remains poor. Here, we report the preclinical studies in pancreatic cancer cells that demonstrate the efficacy of triphendiol (NV-196, a synthetic isoflavene) both as a monotherapy and as a gemcitabine sensitizer. The in-vitro effects of triphendiol on the pancreatic cancer cell lines HPAC and MIAPaCa-2 were determined using cell proliferation, flow cytometry, and western blot analysis. The antiproliferative activity of triphendiol was also investigated in two xenograft models of pancreatic cancer (HPAC and MIAPaCa-2). As a monotherapy, triphendiol-inhibited cell proliferation-induced p53-independent G2/M cell cycle arrest and activation of the intrinsic (mitochondrial) apoptosis pathway. Triphendiol-induced apoptosis was caspase independent and death receptor independent, whereas cell necrosis was caspase mediated. Using combination index analysis, we have shown that pretreatment of pancreatic cancer cells with triphendiol enhanced the cytotoxic effect of gemcitabine, the standard of care used to treat advanced pancreatic cancer. In xenograft models of pancreatic cancer, the rate of tumor proliferation on mice coadministered with triphendiol and gemcitabine was significantly reduced when compared with the corresponding tumor proliferation rates from the respective monotherapy-control and vehicle-control groups. Triphendiol was recently granted Investigational New Drug status by the US Food and Drug Administration. These data justify the commencement of clinical studies investigating the utility of combining triphendiol and gemcitabine in patients with early-stage and late-stage pancreatic cancer.     

姜黄素体内外逆转结肠癌的5-氟尿嘧啶耐药研究及机制探讨

摘要：目的 探究姜黄素在体内外对结肠癌5-氟尿嘧啶（5-FU）耐药的逆转作用及其相关机制。 方法 以SW480结肠癌细胞为亲代细胞,构建5-FU耐药细胞株SW480R,采用MTT法检测SW480R细胞的耐药指数以及不同浓度的姜黄素对SW480R细胞增殖能力的影响;流式细胞术检测姜黄素对SW480R细胞周期和凋亡的影响;Western blot检测姜黄素对SW480R细胞上皮-间充质转化（epithelial-mesenchymal transition, EMT）相关蛋白以及Wnt信号通路相关蛋白的影响;采用裸鼠移植瘤模型检测肿瘤体积变化情况,计算姜黄素的体内抑瘤率,Western blot检测肿瘤组织中相关蛋白变化。结果 SW480R的耐药指数为12.16,姜黄素能够剂量依赖性地抑制SW480R细胞的增殖,阻滞SW480R细胞周期于G0/G1期,以及诱导SW480R细胞凋亡;Western blot结果表明姜黄素能够在体内外抑制EMT和Wnt信号通路的活性;体内实验表明姜黄素能够有效抑制裸鼠移植瘤的生长。结论 姜黄素能够在体内外逆转结肠癌的5-FU耐药,其机制可能是通过调控Wnt信号通路从而抑制EMT的发生。     

单胺氧化酶抑制剂氯吉灵抑制结肠癌的作用及机制研究

目的：研究单胺氧化酶A （monoamine oxidase A,MAO-A）抑制剂氯吉灵（Clorgyline）对结肠癌细胞增殖、转移的作用,以及其对MAO-A的酶活、MAO-A、MMP-2和MMP-9蛋白表达的影响。方法：MTS法检测不同浓度Clorgyline对结肠癌细胞SW480增殖的作用;划痕实验研究Clorgyline对SW480细胞迁移的影响;Transwell实验研究Clorgyline对SW480细胞侵袭的影响;裸鼠移植瘤模型研究Clorgyline对SW480细胞体内增殖的抑制作用;酶活试剂盒检测Clorgyline对裸鼠移植瘤组织中MAO-A的作用;Western blot检测Clorgyline对裸鼠移植瘤组织中的MAO-A、MMP-2和MMP-9蛋白表达的影响。结果：Clorgyline对SW480细胞增殖有抑制作用,且呈现剂量依赖性;Clorgyline 10 μmol·L^-1和20 μmol·L^-1浓度均能够抑制SW480细胞迁移和侵袭能力,与对照组相比具有显著性差异（P<0.01）;Clorgyline 20和40 mg·kg^-1均能够抑制SW480细胞裸鼠移植瘤的生长（P<0.01）,抑制裸鼠移植瘤组织中MAO-A的酶活（P<0.05）,抑制MMP-2和MMP-9蛋白的表达水平,而对MAO-A蛋白的表达水平没有影响。结论：Clorgyline抑制SW480结肠癌细胞的增殖和转移,其机制可能与抑制MAO-A酶活和转移相关蛋白MMP-2、MMP-9的表达有关。     

奥曲肽与氟尿嘧啶联合对人结肠癌细胞SW480增殖抑制作用的研究

目的:研究奥曲肽单用及其与5-氟尿嘧啶(5-FU)联合对人结肠癌细胞SW480的增殖抑制作用。方法:采用MTT比色法测定不同浓度(10-7～10-10mol.L-1)奥曲肽单用及其与5-FU(12.5、25、50μg.mL-1)联合作用SW480后的吸光度值后计算抑制率。结果:奥曲肽各浓度中,以10-10mol.L-1抑制率最高,10-12mol.L-1以下对细胞增殖无抑制作用;奥曲肽与5-FU联合使用对细胞增殖的抑制率明显高于单用组(P<0.01)。结论:奥曲肽能抑制人结肠癌细胞SW480的增殖,并与5-FU有协同作用。     

Inhibition of self-renewal and differentiation of HT-29 cells-derived cancer stem-like cells by scutellarin via Hedgehog signaling pathway

OBJECTIVE To investigate the inhibitory effect of scutellarin on the self-renewal and differentiation of HT-29 cells-derived cancer stem-like cells(HT-29 CSC) in vitro and in vivo, and to explore its mechanism. METHODS The effect of scutellarin on the growth of HT-29 CSC was determined by 3 D Culture assay. The effect of scutellarin on growth and transformation of HT-29 CSC was probed by soft agar colony formation assay. The effect of scutellarin on the differentiation of HT-29 CSC was determined by serum induction differentiation assay in vitro. The effects of scutellarin on the expressions of marker gene Lgr5, target gene c-Myc, proliferation gene CK20 and Nanog gene were measured by quantitative real-time RT-PCR. Investigate the effect of scutellarin on the expression of c-Myc, Gli1, and Lgr5 protein by Western blotting. A subcutaneous xenograft model of colon cancer in nude mice was established and administered by intraperitoneal injection. The change of body weight and tumor size of nude mice were observed every two days. Investigate the effects of scutellarin on the growth of xenograft tumors in nude mice. The expression of CD133, Lgr5, Gli1,Ptch1, c-Myc, Ki67, CK20, Nanog gene in tumors were measured by quantitative real-time RT-PCR. The expression of c-Myc, Gli1, Lgr5, CD133, Ki67 protein were measured by Western blotting. RESULTS Scutellarin can inhibit the growth of HT-29 CSC in 3 D culture. Compared with the solvent control group, scutellarin can significantly inhibit the growth and transformation and differentiation of HT-29 CSC in vitro(P<0.01). The expression levels of marker genes Lgr5, target gene c-Myc, proliferation gene CK20 and Nanog in HT-29 CSC were down-regulated by scutellarin. Scutellarin can reduce the expression of c-Myc, Gli1, and Lgr5 protein in HT-29 CSC.Scutellarin can inhibit the growth of colon cancer xenografts, lower CD133, Lgr5, Gli1, Ptch1, c-Myc, Ki67, CK20, and Nanog mRNA level of xenograft tumors, reduce the expression of c-Myc, Gli1, Lgr5, CD133, and Ki67 protein of xenograft tumors in nude mice. CONCLUSION Scutellarin,which is the main component of scutellaria barbata, can inhibit the differentiation of HT-29 CSC and the mechanism is to inhibit the activity of Hedgehog signaling pathway.     

长链非编码RNA OPA相互作用蛋白5反向转录序列1靶向调控微RNA-128-3p对结直肠癌细胞增殖、侵袭和转移的影响

目的 探究长链非编码RNA OPA相互作用蛋白5反向转录序列1(lncRNA OIP5-AS1)在结直肠癌中的表达情况及靶向调控微RNA-128-3p(miR-128-3p)对结直肠癌细胞增殖、侵袭和转移的影响。方法 采用实时荧光定量PCR(qPCR)定量分析2017年1月至2018年12月在郑州大学人民医院住院并进行手术治疗的38例结直肠癌病人癌组织及相应癌旁组织、结直肠癌细胞系（SW480、SW620、HT-29和LoVo）及人正常结直肠黏膜细胞FHC中lncRNA OIP5-AS1和miR-128-3p的表达。将SW620细胞设为si-OIP5-AS1组、si-NC组、miR-128-3p mimic组、mimic-NC组、miR-128-3p inhibitor+si-OIP5-AS1组和inhibitor-NC+siOIP5-AS1组,采用细胞计数试剂盒（CCK-8）实验和克隆形成实验检测细胞增殖能力,采用划痕实验和transwell实验检测细胞侵袭与迁移能力,采用蛋白质印迹法检测E2F1、细胞周期蛋白D1(Cyclin D1)、波形蛋白（Vimentin）、N-钙黏蛋白（N...     

Platelet-Derived Growth Factor Receptor-α Subunit Targeting Suppresses Metastasis in Advanced Thyroid Cancer In Vitro and In Vivo

Thyroid cancer is the most common endocrine malignancy. Patients with well-differentiated thyroid cancers, such as papillary and follicular cancers, have a favorable prognosis. However, poorly differentiated thyroid cancers, such as medullary, squamous and anaplastic advanced thyroid cancers, are very aggressive and insensitive to radioiodine treatment. Thus, novel therapies that attenuate metastasis are urgently needed. We found that both PDGFC and PDGFRA are predominantly expressed in thyroid cancers and that the survival rate is significantly lower in patients with high PDGFRA expression. This finding indicates the important role of PDGF/PDGFR signaling in thyroid cancer development. Next, we established a SW579 squamous thyroid cancer cell line with 95.6% PDGFRA gene insertion and deletions (indels) through CRISPR/Cas9. Protein and invasion analysis showed a dramatic loss in EMT marker expression and metastatic ability. Furthermore, xenograft tumors derived from PDGFRA gene-edited SW579 cells exhibited a minor decrease in tumor growth. However, distant lung metastasis was completely abolished upon PDGFRA gene editing, implying that PDGFRA could be an effective target to inhibit distant metastasis in advanced thyroid cancers. To translate this finding to the clinic, we used the most relevant multikinase inhibitor, imatinib, to inhibit PDGFRA signaling. The results showed that imatinib significantly suppressed cell growth, induced cell cycle arrest and cell death in SW579 cells. Our developed noninvasive apoptosis detection sensor (NIADS) indicated that imatinib induced cell apoptosis through caspase-3 activation. In conclusion, we believe that developing a specific and selective targeted therapy for PDGFRA would effectively suppress PDGFRA-mediated cancer aggressiveness in advanced thyroid cancers.     

Polydopamine-coated i-motif DNA/Gold nanoplatforms for synergistic photothermal-chemotherapy

The combination of photothermal therapy with chemotherapy has gradually developed into promising cancer therapy. Here, a synergistic photothermal-chemotherapy nanoplatform based on polydopamine (PDA)-coated gold nanoparticles (AuNPs) were facilely achieved via the in situ polymerization of dopamine (DA) on the surface of AuNPs. This nanoplatform exhibited augmented photothermal conversion efficiency and enhanced colloidal stability in comparison with uncoated PDA shell AuNPs. The i-motif DNA nanostructure was assembled on PDA-coated AuNPs, which could be transformed into a C-quadruplex structure under an acidic environment, showing a characteristic pH response. The PDA shell served as a linker between the AuNPs and the i-motif DNA nanostructure. To enhance the specific cellular uptake, the AS1411 aptamer was introduced to the DNA nanostructure employed as a targeting ligand. In addition, Dox-loaded NPs (DAu@PDA-AS141) showed the pH/photothermal-responsive release of Dox. The photothermal effect of DAu@PDA-AS141 elicited excellent photothermal performance and efficient cancer cell inhibition under 808 nm near-infrared (NIR) irradiation. Overall, these results demonstrate that the DAu@PDA-AS141 nanoplatform shows great potential in synergistic photothermal-chemotherapy.