OSU03012 activates Erk1/2 and Cdks leading to the accumulation of cells in the S-phase and apoptosis

OSU03012, a Celecoxib derivative, has been shown to inhibit proliferation and induce apoptosis in human cancer cell lines. However, its underlying mechanisms are not completely understood. In our study, the relationship between cell cycle inhibition and apoptosis induced by OSU03012 was investigated in human oral cancer cell lines. In the premalignant and malignant cell lines, OSU03012-induced growth inhibition, S-phase arrest, and apoptosis were accompanied by a marked increase in the activity of Erk1/2 and Cdk2/cyclin A. Inhibition of Cdks by roscovitine partially blocked OSU03012-induced growth inhibition and apoptosis. Although the activity of cdc2/cyclin B was reduced, expression of constructively active cdc2AF did not reverse OSU03012-induced S-phase arrest. When Erk1/2 was inhibited by U0126 before addition of OSU03012, growth inhibition and apoptosis induced by OSU03012 were attenuated. The levels of the Cdk2/cyclin A were reduced and cells accumulated in the G(0)/G(1) phase. When cells were allowed to accumulate in S-phase before addition of U0126, apoptosis also was attenuated suggesting that Erk1/2 is required for both progression of cells into the S-phase and apoptosis. Expression of constructively active MEK enhanced OSU03012-induced apoptosis. OSU03012 selectively inhibited the proliferation in premalignant and malignant, but not normal human oral cell lines. In conclusion, we show that OSU03012 has potent anti-proliferative and apoptotic activity against premalignant and malignant human oral cells through activation of Erk1/2, and Cdks. OSU0312 may provide unique opportunities for cancer prevention and sensitization of cancer cells to S-phase modalities.     

Decreased NSG3 enhances PD-L1 expression by Erk1/2 pathway to promote pancreatic cancer progress

Inhibiting the functioning of PD-1/PD-L1 to activate human immune system and improve the prognosis of pancreatic cancer (PC) would provide a significant boost to handling the disease. One research found the expression level of NSG3 was reduced in pediatric pilocytic astrocytoma, so is PC and we found NSG3 could regulate the expression of PD-L1. So NSG3 could become a new target for enhancing the immune response to PC. The GEPIA website was employed to analyze the prognoses in PC patients with different NSG3 levels. Immunohistochemistry (IHC) analysis was applied to detect different levels of NSG3 in para-PC and PC tissues. Cell biological function tests (in vitro) were performed and a subcutaneous nude mice tumor model (in vivo) was established to verify the effect of NSG3 on PC. Immunoblotting and RT-qPCR were utilized to demonstrate the inhibiting effect of NSG3 on PD-L1 through regulating Erk1/2 phosphorylation. A subcutaneous C57BL/6 tumor mice model was established to assess the possibility of a synergistic effect of NSG3 expression and the use of an anti-PD-L1 antibody on PC. PC tissues had decreased NSG3 expression levels, which led to poor prognosis. Overexpressing NSG3 suppressed proliferation, invasion and migration capacities of PC cells. On the contrary, knocking-down NSG3 prompted PC malignancy whether in vivo or in vitro. Importantly, NSG3 prevented Erk1/2 phosphorylation to inhibit PD-L1 expression. Additionally, NSG3 and an immune checkpoint inhibitor anti-PD-1 antibody acted synergistically, which enhanced the efficacy of the inhibitor. NSG3 inhibited PD-L1 expression by suppressing Erk1/2 phosphorylation to improve the immune response to PC. NSG3 is, therefore, a potential new diagnostic and prognostic marker, particularly useful in immune checkpoint blockade therapy.     

CD155通过Ras/Erk通路促进肺腺癌细胞增殖及抑制其凋亡的分子机制

目的:研究CD155通过调控Ras/Erk通路对肺腺癌细胞活性、增殖、凋亡的影响,并探讨其作用的分子机制。方法:通过慢病毒转染法构建过表达或敲低CD155的人肺腺癌H23和H522细胞株,qRT-PCR检测肺腺癌细胞中CD155 mRNA表达水平,CCK-8法检测细胞活力,免疫荧光法测定细胞增殖和凋亡水平;Western blot检测PCNA、caspase-3、Ras、Erk1蛋白的表达及活化水平;小分子药物FTI 277或FR 180204处理过表达CD155的H23和H522细胞抑制Ras及Erk通路,检测对细胞活性、增殖、凋亡的影响;采用慢病毒共转染的方法构建CD155与SPRY2共同过表达的H23细胞系,免疫共沉淀法检测细胞中SPRY2、CD155蛋白间的结合关系,以同样的方法检测对细胞活性、增殖、凋亡的影响。结果:慢病毒转染肺腺癌H23和H522细胞可上调或下调细胞中CD155的表达,差异具有统计学意义（P＜0.05）;CD155过表达可促进肺腺癌细胞活性、增殖及PCNA蛋白的表达,抑制细胞凋亡及caspase-3的活化,敲低CD155则表现出相反的作用,差异具有统计学意义（P＜0.05）;CD155过表达可激活Ras和Erk1,敲低CD155则抑制Ras和Erk1的激活,差异具有统计学意义（P＜0.05）;抑制Ras和Erk通路可抑制过表达CD155引起的细胞增殖及活性的促进作用,缓解过表达CD155诱导的细胞凋亡,差异具有统计学意义（P＜0.05）;SPRY2过表达逆转CD155过表达对H23细胞增殖及活性的促进作用,抑制对Ras/Erk通路激活的促进作用,差异具有统计学意义（P＜0.05）。结论:CD155可通过提高Ras/Erk通路的激活程度,促进肺腺癌细胞在体外的增殖及活性,其作用机制可能是部分由CD155与SPRY2蛋白发生相互作用,降低了SPRY2蛋白对Ras/Erk通路的抑制作用引起的。     

Hoechst33342/PI双染法和TUNEL染色技术检测神经细胞凋亡的对比研究

目的： 利用Hoechst33342/PI双染法和原位末端标记法(TUNEL)染色检测纳米二氧化硅(nm-SiO2)对神经细胞凋亡的影响,比较两种检测方法的优缺点。方法：以体外培养的人神经母细胞瘤SK-N-SH为研究对象,15和30 nm粒径的nm-SiO2(剂量为2.5、5、10 μg/mL)分别处理细胞24 h,另设1~5 μm SiO2组和溶剂对照组,采用Hoechst33342/PI双染法和TUNEL染色检测各处理组对SK-N-SH细胞凋亡的影响。结果：与对照组相比,两种检测方法分析均显示了nm-SiO2处理组SK-N-SH细胞凋亡率显著增加(P<0.05),且具有尺寸、剂量依赖性,而微米级SiO2对凋亡的影响不显著(P>0.05)。结论：nm-SiO2能诱导SK-N-SH细胞凋亡。Hoechst33342/PI双染法特异性高,简单易行;TUNEL法灵敏度高,能检测少量的细胞凋亡,但成本较高,两种方法可结合使用以便更加准确的检测神经细胞的凋亡。     

雷帕霉素诱导人肝癌细胞BEL-7402凋亡中Bcl-2作用研究

目的探讨雷帕霉素(rapamycin,RAPA)体外对肝癌BEL-7402细胞生长抑制及诱导细胞凋亡中的作用及Bcl-2变化在凋亡机制中的意义。方法以5、10、20、30、40和50nmol/L不同浓度的RAPA作用于体外培养的BEL-7402细胞,MTT法检测细胞生长抑制率,应用流式细胞仪检测细胞凋亡,Hoechst33258荧光染色法观察细胞凋亡时的形态学变化,Westernblot观察Bcl-2、Bcl-xl和bax等凋亡相关表达变化。结果RAPA可显著抑制BEL-7402细胞的生长,诱导细胞发生凋亡,并呈现出明显的量-效与时-效关系。RAPA作用肝癌细胞BEL-740248h后,在Hoechst33258荧光染色图片上可见核浓缩及核碎裂等典型的细胞凋亡特征,凋亡过程中伴有抗凋亡蛋白Bcl-2、Bcl-xl表达的降低和促凋亡蛋白bax上调。结论RAPA可能通过诱导抗凋亡蛋白Bcl-2、Bcl-xl表达的降低和促凋亡蛋白bax表达上调而诱导凋亡发生,抑制BEL-7402细胞的生长。     

PKR negatively regulates leukemia progression in association with PP2A activation,Bcl-2 inhibition and increased apoptosis

Reduced expression and activity of the proapoptotic, double-stranded RNA-dependent protein kinase, PKR (protein kinase R) is observed in breast, lung and various leukemias, suggesting that loss of PKR potentiates transformation. Now we report that decreased PKR activity inhibits chemotherapy-induced apoptosis of leukemia cells both in vitro and in vivo. Inhibition of PKR expression or activity reduces protein phosphatase 2A (PP2A) activity, a B-cell lymphoma 2 (Bcl-2) phosphatase, resulting in enhanced Bcl-2 phosphorylation. Thus, inhibition of PKR activity leads to hyperphosphorylation of Bcl-2, stabilization of Bcl-2/Bax interaction and decreased Bax insertion into the outer mitochondrial membrane. Treatment with the PP2A activator, FTY720, restores Bcl-2 dephosphorylation and apoptosis in cells with reduced PKR expression following stress. Significantly, xenografts of REH leukemic cells with reduced PKR display significantly increased tumor volume, increased resistance to doxorubicin treatment and shorter survival. Importantly, FTY720 treatment restores sensitivity to chemotherapy and prolongs overall survival of these mice. Collectively, these findings suggest that PP2A activation is a downstream target of PKR and the PKR/PP2A signaling axis is required for rapid and potent stress-induced apoptosis. Importantly, loss of PKR promotes leukemia progression and may serve as a biomarker for predicting chemosensitivity.     

Ruxolitinib induces apoptosis of human colorectal cancer cells by downregulating the JAK1/2-STAT1-Mcl-1 axis

Under pathological conditions, the Janus kinase (JAK)/STAT signaling pathway can regulate the proliferation, differentiation and migration of tumor cells, including colorectal cancer (CRC). CRC is the third major types of cancer among males and the second among females worldwide. In China, CRC is the fifth common cancer among both males and females. Western blotting, flow cytometry, RNA interference, immunoprecipitation, xenografts models, and immunohistochemical staining were carried out to evaluate the possible mechanisms of acton of ruxolitinib. The present data suggested that ruxolitinib can suppress CRC cell proliferation by inducing apoptosis. Firstly, JAK1/2-STAT1 was identified as the target of ruxolitinib. Then, ruxolitinib downregulated myeloid cell leukemia-1 (Mcl-1) mRNA level and decreased its protein level, which enabled Bak to trigger CRC apoptosis. Furthermore, ruxolitinib exerted potent activity against CRC xenograft growth in vivo. High expression of phosphorylated STAT1 (S727) was also confirmed in 44 pairs of human colon carcinoma and adjacent normal tissues. Taken together, the results showed that ruxolitinib decreased JAK1/2-STAT1-Mcl-1 protein level and effectively suppressed CRC cell proliferation in vitro and in vivo. Therefore, ruxolitinib could be a promising anticancer agent for CRC treatment.     

Rapamycin regulates Akt and ERK phosphorylation through mTORC1 and mTORC2 signaling pathways

Numerous studies have shown that mammalian target of rapamycin (mTOR) inhibitor activates Akt signaling pathway via a negative feedback loop while inhibiting mTORC1 signaling. In this report, we focused on studying the role of mTORC1 and mTORC2 in rapamycin‐mediated Akt and ERK phosphorylation, and the antitumor effect of rapamycin in cancer cells in combination with Akt and ERK inhibitors. Moreover, we analyzed the effect of mTORC1 and mTORC2 on regulating cell cycle progression. We found that low concentrations rapamycin increased Akt and ERK phosphorylation through a mTORC1‐dependent mechanism because knockdowned raptor induced the activation of Akt and ERK, but higher doses of rapamycin inhibited Akt and ERK phosphorylation mainly via the mTORC2 signaling pathway because that the silencing of rictor led to the inhibition of Akt and ERK phosphorylation. We further showed that mTORC2 was tightly associated with the development of cell cycle through an Akt‐dependent mechanism. Therefore, we combined PI3K and ERK inhibitors prevent rapamycin‐induced Akt activation and enhanced antitumor effects of rapamycin. Collectively, we conclude that mTORC2 plays a much more important role than mTORC1 in rapamycin‐mediated phosphorylation of Akt and ERK, and cotargeting AKT and ERK signaling may be a new strategy for enhancing the efficacy of rapamycin‐based therapeutic approaches in cancer cells. © 2010 Wiley‐Liss, Inc.     

Dexrazoxane protects against doxorubicin-induced cardiomyopathy: upregulation of Akt and Erk phosphorylation in a rat model

Purpose  Dexrazoxane (DZR), a clinically approved cation chelator, is effective in reducing doxorubicin (DOX)-induced heart damage, yet its cardioprotective mechanism is not fully understood. We aimed to investigate the effects of DZR on the activation of Akt and Erk 1/2 signals in a rat model of DOX-induced cardiomyopathy. Methods  Male Sprague–Dawley rats received weekly DOX injection (2.5 mg/kg) for 6 weeks, with or without DZR pretreatment at a dose ratio of 20:1. The ventricular functions of these animals were monitored at week 6, 9 and 11 by echocardiography. At week 11, their heart morphology was studied by light and electron microscopy. Phosphorylation of Akt and Erk in heart tissues was measured by Western blot analysis. Results  DOX caused myocardial damage with compromised left ventricular function, increased myocardium injury and reduced phosphorylation of Akt and Erk. DZR exerted a significant cardioprotective effect in terms of improved fractional shortening, cardiac output and cardiomyopathy score at one or more time points. We also provided the first evidence that dexarazoxane-treated animals had increased levels of Akt and Erk activation, whilst total Akt and Erk remained unchanged. Conclusions  Our results showed that the cardioprotective effect of dexarazoxane has been sustained beyond the treatment period. The data also suggested that activation of the Akt and Erk signaling pathways was regulated in the course of DOX-induced cardiomyopathy and protection by DZR. Ping Xiang and Hai Yan Deng have equal contribution to this study.     

TRIP-Br1 oncoprotein inhibits autophagy,apoptosis, and necroptosis under nutrient/serum-deprived condition

TRIP-Br1 oncogenic protein has been shown to have multiple biological functions in cells. In this study, we demonstrate that TRIP-Br1 functions as an oncoprotein by inhibiting autophagy, apoptosis, and necroptosis of cancer cells and eventually helping them to survive under the nutrient/serum starved condition. TRIP-Br1 expression level was significantly increased in conditions with low levels of nutrients. Nutrient depleted conditions were induced by culturing cancer cells until they were overcrowded with high cell density or in media deprived of glucose, amino acids, or serum. Among them, serum starvation significantly enhanced the expression of TRIP-Br1 only in all tested breast cancer cell lines (MCF7, MDA-MB-231, T47D, MDA-MB-435, Hs578D, BT549, and MDA-MB-435) but not in the three normal cell lines (MCF10A, HfCH8, and NIH3T3). As compared with the control cells, the introduction of TRIP-Br1 silencing siRNA into MCF7 and MDA-MB-231 cells accelerated cell death by inducing apoptosis and necroptosis. In this process, TRIP-Br1 confers resistance to serum starvation-induced cell deaths by stabilizing the XIAP protein and inhibiting cellular ROS production. Moreover, our data also show that the intracellular increase of TRIP-Br1 protein resulting from serum starvation seems to occur in part through the blockage of PI3K/AKT signaling pathway.     

Checkpoint kinase 1-mediated phosphorylation of Cdc25C and bad proteins are involved in antitumor effects of loratadine-induced G2/M phase cell-cycle arrest and apoptosis

In this study, we first demonstrated that loratadine (LOR), a promising world widely used oral anti-histamine, effectively inhibits growth of tumors derived from human colon cancer cells (COLO 205) in an in vivo setting. In vitro study demonstrated that the anti-tumor effects of LOR in COLO 205 cells were mediated by causing G(2)/M phase cell growth cycle arrest and caspase 9-mediated apoptosis. Cell-cycle arrest induced by LOR (75 microM, 24 h) was associated with a significant decrease in protein levels of cyclin B1, cell division cycle (Cdc) 25B, and Cdc25C, leading to accumulation of Tyr-15-phosphorylated Cdc2 (inactive form). Interestingly, LOR (75 microM, for 4 h) treatment also resulted in a rapid and sustained phosphorylation of Cdc25C at Ser-216, leading to its translocation from the nucleus to the cytoplasm because of increased binding with 14-3-3. We further demonstrated that the LOR-induced Cdc25C (Ser-216) phosphorylation was blocked in the presence of checkpoint kinase 1 (Chk1) specific inhibitor (SB-218078). The cells treated with LOR in the presence of Chk1 specific inhibitor (SB-218078) were then released from G(2)/M arrest into apoptosis. These results implied that Chk1-mediated phosphorylation of Cdc25C plays a major role in response to LOR-mediated G(2)/M arrest. Although the Chk1-mediated cell growth arrest in response to DNA damage is well documented, our results presented in this study was the first report to describe the Chk1-mediated G(2)/M cell-cycle arrest by the histamine H1 antagonist, LOR.     

EDAG-1 promotes proliferation and invasion of human thyroid cancer cells by activating MAPK/Erk and AKT signal pathways

Erythroid differentiation-associated gene (EDAG) is differentially expressed in normal hematopoietic progenitor/stem cells and a variety of embryonic tissues. High EDAG-1 expression is also found in human thyroid cancer cells and peripheral blood of patients with leukemia, but its functional significance was unclear. Current study aims to further clarify the expression pattern of EDAG-1 and tests its roles in proliferation and invasion of human thyroid cancer cells in vitro and in vivo. To this end, we have performed gain-of-function and loss-of-function studies to clarify how EDAG-1 regulates the proliferation, invasion, and adhesion ability of human thyroid cancer cells SW579cells. We found that overexpression of EDAG-1 promoted the proliferation, invasion, and adhesion of human thyroid cancer cells, whereas silencing of EDAG-1 reversed all these changes and reduced the tumorigenesis risk of nude mice. Mechanistically, we found that overexpression of EDAG-1 activated the MAPK/Erk and AKT signal pathways. These findings provide novel insights of the role of EDAG-1 in thyroid tumors, and may have direct clinical implication.     

Aquaporin 8 Involvement in Human Cervical Cancer SiHa Migration via the EGFR-Erk1/2 Pathway

Overexpression of aquaporins (AQPs) has been reported in several human cancers. Epidermal growth factor receptor (EGFR)-extracellular signal-regulated kinases 1/2 (Erk1/2) are associated with tumorigenesis and cancer progression and may upregulate AQP expression. In this study, we demonstrated that EGF (epidermal growth factor) induces SiHa cells migration and AQP8 expression. Wound healing results showed that cell migration was increased by 2.79-1.50-fold at 24h and 48h after EGF treatment. AQP8 expression was significantly increased(3.33-fold) at 48h after EGF treatment in SiHa cells. An EGFR kinase inhibitor, PD153035, blocked EGFinduced AQP8 expression and cell migration and AQP8 expression was decreased from 1.59-fold (EGF-treated) to 0.43-fold (PD153035-treated) in SiHa. Furthermore, the MEK (MAPK (mitogen-activated protein kinase)/ Erk (extracellular signal regulated kinase)/Erk inhibitor U0126 also inhibited EGF-induced AQP8 expression and cell migration. AQP8 expression was decreased from 1.21-fold (EGF-treated) to 0.43-fold (U0126-treated).Immunofluorescence microscopy further confirmed the results. Collectively, our findings show that EGF induces AQP8 expression and cell migration in human cervical cancer SiHa cells via the EGFR/Erk1/2 signal transduction pathway.     

E1A inhibits the proliferation of human cervical cancer cells (HeLa cells) by apoptosis induction through activation of HER-2/Neu/Caspase-3 pathway

OBJECTIVE: This study is to investigate the inhibitory effect of E1A gene on the cell proliferation of HeLa cells and its mechanism related to apoptosis. METHODS: MTT assay and soft agar colony formation assay were employed to justify the inhibition activity of E1A on the proliferation of HeLa cells transfected with E1A gene. Western Blot, RT-PCR and Real-time quantitative RT-PCR were used to detect the gene expression of E1A, HER-2/Neu and Caspase-3 in HeLa cells, respectively. The Caspase-3 activity was monitored by ApoAlert Caspase-3 Assay. The redistribution of cell cycles and apoptosis of HeLa cells regulated by E1A expression were evaluated by flow cytometry. RESULTS: E1A expression significantly inhibits the cell proliferation and anchorage-independent cell growth of HeLa, with the respective highest inhibition rate of 40.7% and 43.4% (P < 0.01). HER-2/Neu expression in HeLa was significantly down-regulated by E1A, while the protein expression and activity of Caspase-3 was up-regulated by E1A expression. Flow cytometry revealed that E1A transfection in HeLa increased the cell number at G1 stage and simultaneously decreased the cell number at S stage. E1A transfection induced 8.71% of HeLa cells at apoptosis status. CONCLUSIONS: E1A significantly inhibits the cell proliferation of HeLa by the apoptosis induction through HER-2/Neu/Caspase-3 pathway. These results encourage us to continue an in-vivo study and preclinical development of LPD-E1A as a novel gene therapeutic agent for human cervical cancer.     

A novel Mcl1 variant inhibits apoptosis via increased Bim sequestration

Members of the Bcl-2 protein family are frequently deregulated in tumors as they critically control cell death induction in mammalian cells. Alterations of these proteins may cause resistance to chemotherapy-induced cell death and immune responses. By serendipity we cloned a variant of the anti-apoptotic Bcl2-family member Myeloid cell leukemia-1 (Mcl1) from human neuroblastoma and leukemia cells. This Mcl1L variant lacks a 45 bp sequence that codes for 15 highly conserved amino acids ranging from Gly158 to Asp172. This region is part of the so called PEST-sequence of Mcl1L and contains two phosphorylation sites (Ser159 and Thr163) that regulate Mcl1L stability. A caspase 3/caspase 8 cleavage site at Asp157 which has been reported to be critical for death-receptor-induced apoptosis and for the conversion of Mcl1L into a pro-apoptotic protein is also missing in this novel variant. Importantly, Mcl1L_{delGly158-Asp172} bound significantly more pro-apoptotic Bim compared to Mcl1L and showed increased anti-proliferative and anti-apoptotic activity compared to Mcl1L during death receptor-induced cell death. This suggests that this novel Mcl1L variant efficiently protects tumor cells against extrinsic death signalling and therefore may provide a survival advantage for highly aggressive tumors.     

集落刺激因子1 受体介导Bax 和Bcl-2 表达对人鼻咽癌6-10B细胞凋亡的影响

目的: 研究过表达集落刺激因子1 受体（colony stimulating factor-1 receptor,CSF-1R）对人鼻咽癌(nasopharyngeal carcinoma,NPC)6-10B细胞凋亡的抑制作用及其与Bax和Bcl-2 表达之间的关系。方法: 体外利用慢病毒构建的CSF-1R过表达载体LV-CSF1R(16957-1)转染到人鼻咽癌6-10B细胞中,实验分转染组和对照组;采用实时荧光定量PCR 及Western blotting 检测转染后两组细胞中CSF-1R、Bcl-2、Bax的表达情况;CCK-8 法检测两组细胞的增殖;流式细胞术检测两组细胞的凋亡情况。结果:转染组的6-10B细胞中其CSF-1 mRNA表达水平明显高于对照组(7.01±0.23 vs 0.09±0.03,P<0.01); Bax mRNA表达水平显著下调(P<0.01),而Bcl-2 mRNA表达水平显著上调(P<0.01)。转染组的6-10B细胞中CSF-1 蛋白表达水平明显高于对照组;Bax蛋白表达水平显著下调,而Bcl-2 蛋白表达水平稍上调。与对照组相比,转染组6-10B细胞的增殖活力明显提高(P<0.01);凋亡率显著降低[(10.82±0.75) % vs (17.11 ±0.46)%,P<0.05]。结论:过表达CSF-1R 可以通过调节Bax/Bcl-2 之间的比例关系来促进鼻咽癌6-10B细胞的恶性增殖,并抑制细胞凋亡。     

hnRNP A2/B1在胃癌中的表达及其临床意义

目的：在既往的胃癌蛋白质组研究中我们已发现hnRNP A2/B1具有较高表达,本试验进一步探讨hnRNPA2/B1在胃癌中的表达情况及其与胃癌临床病理特征的关系。方法：用免疫组织化学方法检测122例胃癌患者的胃癌组织及癌旁正常胃粘膜中hnRNP A2/B1蛋白的表达。结果：hnRNP A2/B1在胃癌组织中核表达的阳性率为92.6%（113/122）,其中伴有胞浆表达的阳性率为7.3%（9/122）。在癌旁非瘤组织中核表达阳性率为87.7%（107/122）,未见胞浆表达。hnRNP A2/B1的表达状态与胃癌临床病理特征无关联。结论：在胃癌及癌旁非瘤组织中均可发现hnRNP A2/B1核表达,hnRNP A2/B1不能作为肿瘤相关的分子标志物。