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  • 1.

    【2hr】The role of oncogenic Notch2 signaling in cancer: a novel therapeutic target

    包量

    机译 Notch2致癌信号在癌症中的作用：一种新型治疗靶点
    摘要：Deregulated Notch signaling is a key factor thought to facilitate the stem-like proliferation of cancer cells, thereby facilitating disease progression. Four subtypes of Notch receptor have been described to date, with each playing a distinct role in cancer development and progression, therefore warranting a careful and comprehensive examination of the targeting of each receptor subtype in the context of oncogenesis. Clinical efforts to translate the DAPT, which blocks Notch signaling, have been unsuccessful due to a combination of serious gastrointestinal side effects and a lack of complete blocking efficacy. There is therefore a clear need to identify better therapeutic strategies for targeting and manipulating Notch signaling. Notch2 is a Notch receptor that is commonly overexpressed in a range of cancers, and which is linked to a unique oncogenic mechanism. Successful efforts to block Notch2 signaling will depend upon doing so both efficiently and specifically in patients. As such, in the present review we will explore the role of Notch2 signaling in the development and progression of cancer, and we will assess agents and strategies with the potential to effectively disrupt Notch2 signaling and thereby yield novel cancer treatment regimens.
  • 2.

    【2hr】Key indexes and the emerging tool for tumor microenvironment editing

    包量

    机译 肿瘤微环境编辑的关键指标和新兴工具
    摘要：Many cancer management approaches including immunotherapies can not achieve desirable therapeutic efficacies if targeting tumors alone or could not effectively reach tumor cells. The concept of tumor microenvironment and its induced gene reprogramming have largely extended our current understandings on the determinants of tumor initiation/progression and fostered our hope in establishing first-line therapies targeting cancer microenvironment or adjuvant therapies enhancing the efficacies of existing oncotherapeutic modalities such as immunotherapies for efficient cancer management. This review identifies key indexes of tumor microenvironment, i.e., hypoxia, acidosis, hypo-nutrition and inflammation, which collectively determine the feature and the fate of adjacent tumor cells, and proposes cold atmospheric plasma, the fourth state of matter that is largely composed of various reactive oxygen and nitrogen species, as a promising tool for tumor microenvironment editing. We propose that cold atmospheric plasma represents an emerging onco-therapeutic strategy alone or complementing existing treatment approaches given its multi-modal nature through tumor microenvironment modulation.
  • 3.

    【2hr】The potential of brentuximab vedotin, alone or in combination with current clinical therapies, in the treatment of testicular germ cell tumors

    包量

    机译 单独或与当前临床疗法联合使用brentuximab vedotin在治疗睾丸生殖细胞肿瘤中的潜力
    摘要：Testicular germ cell tumors (TGCTs) are the commonest tumors in young men. With the advancement of chemotherapies, most TGCTs are successfully cured, even when diagnosed at an advanced and metastatic stage. However, a proportion of often young patients, median age 35-40, with advanced disease are not cured and will inevitably die. Therefore, there is an unmet need in this small population of young patients who are candidates for experimental approaches. We investigated a new therapeutic option for this group of patients, aiming to significantly improve their outcome. In recent years, many targeted therapies have been developed which demonstrated high efficacy and low toxicity. Brentuximab vedotin, a monomethyl auristatin E conjugated CD30 antibody, targets CD30 to kill cancer cells. As a large proportion of TGCTs express CD30, in particular embryonal carcinomas, we investigated in vitro the efficacy of brentuximab vedotin in treating TGCTs as a single therapy and in combination with commonly used chemotherapy drugs. We determined CD30 expression levels in 12 TGCT cell lines, including three cisplatin resistant sublines. In general, the efficiency of cancer cell inhibition by brentuximab vedotin correlates with CD30 expression, but there were some exceptions. We also determined the efficacy of brentuximab vedotin in combination with commonly used chemotherapy drugs and found synergistic/additive effects with etoposide, paclitaxel and SN-38. However, cisplatin, the most commonly used chemotherapy drug in TGCT treatment, exhibited antagonism and we showed that cisplatin selectively kills CD30 positive cells. We also found that certain agents, which have been reported to induce CD30 expression in other human malignant diseases, including DNA demethylation drugs, methotrexate and CD30 ligands, were unable to enhance CD30 expression or brentuximab vedotin efficacy in TGCT cells. This study will help to design clinical trials using brentuximab vedotin for the treatment of TGCTs, either as a single agent or in combination with current clinical therapies.
  • 4.

    【2hr】Changes in the intestinal microecology induced by bacillus subtilis inhibit the occurrence of ulcerative colitis and associated cancers: a study on the mechanisms

    包量

    机译 枯草芽孢杆菌引起的肠道微生态变化抑制溃疡性结肠炎和相关癌症的发生：机理研究
    摘要：This study aimed to explore how changes in intestinal floras caused by Bacillus subtilis (Bs) inhibited occurrence of ulcerative colitis (UC) and associated cancers. Bs was used as an intervention in an azoxymethane (AOM)/dextran sodium sulfate sodium (DSS) animal model. Stool specimens were analyzed for changes in intestinal floras. Disease activity index (DAI) scores, body mass indices, cancer counts, and other indices were calculated, while changes in the colon mucosa were observed. Compared with AOM/DSS group, carcinogenesis significantly reduced and intestinal inflammations and DAI score alleviated; diversity, evenness, and number of species of floras significantly increased; and relative abundances of Rikenellaceae and Lactobacillus increased when UC developed into cancers in the AOM/DSS + Bs group. Colon epitheliums in the mice were severely damaged in the AOM/DSS group, while mucosae were repaired in the AOM/DSS + Bs group. The mRNA expression levels of IL-6 and IL-17a were lower while those of IL-10 and TGF-β1 were higher, and the expression level of Ki-67 decreased while that of caspase 3 increased in the AOM/DSS + Bs group. Bs intervention could alter the structure of intestinal floras, repair the mucosal barrier, adjust immunity, and reduce the incidence of cancer in the AOM/DSS animal model.
  • 5.

    【2hr】Polyene phosphatidylcholine protects against radiation induced tissue injury without affecting radiotherapeutic efficacy in lung cancer

    包量

    机译 多烯磷脂酰胆碱可防止辐射引起的组织损伤，而不会影响肺癌的放射治疗功效
    摘要：Chemoradiotherapy in inoperable non-small cell lung cancer (NSCLC) is standard, but accompanied by undesirable adverse effects such as radiation pneumonitis. Polyene phosphatidylcholine (PPC) is a hepatoprotective agent and can be used as nutritional adjuvant to chemotherapy. We aimed to investigate influence of PPC on tumor radiosensitivity as well as radiation therapy related injury in healthy tissues. Thus, a retrospective analysis was carried out in 133 NSCLC patients to assess impact of daily PPC administration on radiation pneumonitis. PPC effects on radiation related tissue injury were additionally investigated in mice receiving total body irradiation. Influence of PPC on tumor radiosensitivity was further evaluated using tumor xenografted mice, lewis lung carcinoma (LLC) and A549 cell lines. Uni- and multivariate analyses suggested that daily PPC intake is significantly associated with reduced risk in developing symptomatic radiation pneumonitis in NSCLC patients. In comparison to patients without PPC supplementation, patients who received PPC benefited from a slower decline in lung function post radiotherapy. Total body irradiation in mice further confirmed that PPC administration protected against radiation induced fatal tissue damage and this protective effect was directly linked to increased cellular antioxidant defense. Radiation resulted in significant growth inhibition of cultured LLC and A549 cells as well as of LLC xenografted tumors, however, this was not affected by PPC treatment. In conclusion, PPC protects against radiation induced injury of healthy tissues and thus may serve as meaningful adjuvant for radiotherapy in NSCLC as well for other cancer entities to dampen adverse effects.
  • 6.

    【2hr】Overexpression of MEF2D contributes to oncogenic malignancy and chemotherapeutic resistance in ovarian carcinoma

    包量

    机译 MEF2D的过表达有助于卵巢癌的致癌性和化疗耐药性
    摘要：The transcription factor MEF2 promotes survival in various cell types and a number of studies indicate that abnormal regulation of MEF2 is linked to oncogenicity in several carcinomas. We have found that MEF2D, a member of the MEF2 family, is upregulated in Ovarian Cancer (OC). Immunohistochemistry analysis of tumor sections of 402 OC patients revealed that MEF2D is significantly elevated at the protein level. We have also found that the expression level of MEF2D is associated with cisplatin-resistance and poor prognosis by a retrospective analysis. Furthermore, Downregulation of MEF2D by siRNA reduces proliferation and invasiveness of OC cells SKOV3 and OVCAR3, induces apoptosis in vitro, and abolishes OVCAR3 tumorigenicity in xenograft model. Mechanistic study via ChIP analysis identified two of MEF2D-targeted genes, HPSE and IKBKE, which are associated with tumor invasion and chemotherapy-resistance, in accord with MEF2D expression in OC. Remarkably, knock-down of MEF2D invariably lead to the downregulation of IKBKE and reversed cisplatin (DDP)-resistance in cisplatin-resistant cells SKOV3-DDP. Our results suggest that MEF2D promotes malignant biological behaviors and cisplatin-resistance in OC and establish MEF2D as a new therapeutic target in OC treatment.
  • 7.

    【2hr】Urine protein biomarkers for the detection, surveillance, and treatment response prediction of bladder cancer

    包量

    机译 尿蛋白生物标志物，用于膀胱癌的检测，监测和治疗反应预测
    摘要：The “gold standard” diagnostic procedure for bladder cancer is cystoscopy, a technique that can be invasive, expensive, and a possible cause of urinary tract infection. Unlike techniques such as histology, PCR, and staining, assays for protein biomarkers lend themselves well to the creation of efficient point-of-care tests, which are easy to use and yield fast results. A couple of urine-based tests have been approved by the U.S. FDA, but these tests suffer from low sensitivity. Hence, there is clearly a need for more reliable non-invasive biomarkers of bladder cancer. Urinary biomarkers are particularly attractive due to the direct contact of the urine with the urothelial tumor and the ease of sample collection. With these considerations, this review aims to provide a comprehensive listing of the most promising protein biomarkers of bladder cancer in urine. Biomarkers are organized by their potential role in detection, surveillance, or monitoring of treatment response. The purpose of this review is to assess progress towards the goal of identifying ideal urinary proteins for use in each of the above three biomarker applications in bladder cancer.
  • 8.

    【2hr】Pivotal role of microRNA-138 in human cancers

    包量

    机译 microRNA-138在人类癌症中的关键作用
    摘要：Aberrant expression of certain microRNAs (miRNAs) has been implicated in cancers as a promising druggable target due to the fact that a modulation of the deregulated single miRNA seems to revert the therapeutically unfavorable gene expressions in cancer cell by targeting multiple genes. Global miRNA profiling from a number of patient cohorts in various type of human cancers has identified miR-138 as a signature of tumor suppressor that are down-regulated in most types of human cancer. As a tumor suppressor, miR-138 can inhibit oncogenic proteins by directly bind to their mRNAs. However, in rare cases of cancer stem cell population from glioblastoma, miR-138 seems to be down-regulated and plays an oncogenic function. This review will summarize accumulating evidence that has shown the expression and functional role of miR-138 in various human cancers with its target genes and pathways in a hope to find a better therapeutic option to treat human cancers.
  • 9.

    【2hr】The miR-873/NDFIP1 axis promotes hepatocellular carcinoma growth and metastasis through the AKT/mTOR-mediated Warburg effect

    包量

    机译 miR-873 / NDFIP1轴通过AKT / mTOR介导的Warburg效应促进肝细胞癌的生长和转移
    摘要：Hepatocellular carcinoma (HCC) progression depends on cellular metabolic reprogramming as both direct and indirect consequence of oncogenic lesions. However, the underlying mechanisms are still understood poorly. Here, we report that miR-873 promotes Warburg effect in HCC cells by increasing glucose uptake, extracellular acidification rate (ECAR), lactate production, and ATP generation, and decreasing oxygen consumption rate (OCR) in HCC cells. Mechanistically, we show that miR-873 activates the key glycolytic proteins AKT/mTOR via targeting NDFIP1 which triggers metabolic shift. We further demonstrate that enhanced glycolysis is essential for the role of miR-873 to drive HCC progression. By using immunohistochemistry analysis, we show a link between the aberrant expression of miR-873, NDFIP1, and phospho-AKT in clinical HCC samples. We also found that miR-873 was up-regulated by HIF1α, a critical glycolysis-related transcription factor. However, BAY 87-2243, a HIF1α specific inhibitor, blocks miR-873 mediated tumor growth and metastasis in nude mice. Collectively, our data uncover a previously unappreciated function of miR-873 in HCC cell metabolism and tumorigenesis, suggesting that targeting miR-873/NDFIP1 axis could be a potential therapeutic strategy for the treatment of HCC patients.
  • 10.

    【2hr】Antitumor activity of NKG2D CAR-T cells against human colorectal cancer cells in vitro and in vivo

    包量

    机译 NKG2D CAR-T细胞在体外和体内对人大肠癌细胞的抗肿瘤活性
    摘要：Colorectal cancer is one of the most common malignancies worldwide, as it is often diagnosed at an advanced stage. Chimeric antigen receptor (CAR) T cell therapy has demonstrated remarkable success and emerged as one of the most promising therapeutic strategies in multiple malignancies. The purpose of this study was to investigate the anti-tumor activity of NKG2D CAR-T cells against human colorectal cancer cells. A non-viral third-generation NKG2D CAR was constructed, and subsequently transduced into T cells to obtain the NKG2D CAR-T cells. In vitro, NKG2D CAR-T cells showed cytotoxicity against human colorectal cancer cells in a dose-dependent manner compared with untransduced T cells. In addition, IL-2 and IFN-γ secreted by these cells were significantly higher than those by untransduced T cells. In vivo, NKG2D CAR-T cells significantly suppressed tumor growth, reduced tumor sizes and extended overall survival of mice in a xenograft model of HCT-116 cells. Furthermore, human NKG2D-positive lymphocytes infiltration could be found in the tumor sections of NKG2D CAR-T cells-treated mice. There were no severe pathological changes found in vital organs in any of the treatment groups. NKG2D CAR-T cells showed excellent killing effect and represented a promising immunotherapeutic strategy against human colorectal cancer.
  • 11.

    【2hr】Acid microenvironment promotes cell survival of human bone sarcoma through the activation of cIAP proteins and NF-κB pathway

    包量

    机译 酸性微环境通过激活cIAP蛋白和NF-κB途径促进人骨肉瘤的细胞存活
    摘要：Extracellular acidification is a very common cause of stress in tumor microenvironment and of Darwinian pressure. In acid areas of the tumor, most cancer cells are-albeit slowly proliferating-more resistant to cell death than those in well-perfused regions. Tumor acidosis can directly regulate the expression of pro-survival proteins since a low extracellular pH activates the caspase-dependent cell death machinery. This mechanism has never been explored in bone sarcomas. We cultured osteosarcoma and Ewing sarcoma cells under low pH (pH 6.5), and we performed deep-sequencing and protein analysis. Both in in vitro and in vivo models, acidification activity enhanced tumor cells survival. However, we did not observe any change in ERK1 phosphorylation. On the contrary, both at the mRNA and protein level, we found a significant induction of TRAF adaptor proteins and of cIAP proteins (BIRC2 and/or BIRC3). As a consequence, the downstream nuclear transcription factor kappa B (NF-κB) survival pathway was increased. Furthermore, the treatment with the cIAP inhibitor LCL161 reverted the protection from apoptosis under low pH. In vitro results were confirmed both in Ewing sarcoma xenograft and in osteosarcoma patients, since the analysis of tumor tissues demonstrated that the levels of expression of TRAF1 or NF-κB1 significantly correlate with the level of expression of the vacuolar ATPase (V-ATPase), the most important proton pump in eukaryotes. Moreover, in the tissue sections of xenograft model, the nuclear translocation of RelB, a key subunit of the NF-κB transcriptional complex, localized in the tumor region that also corresponded to the acid microenvironment associated with the highest levels of expression of LAMP2 and V-ATPase, in the internal area of the tumor, as revealed by immunohistochemistry. Our data confirm that tumor acid microenvironment activates a stress-regulated switch to promote cell survival of bone sarcoma, and support the hypothesis that this mechanism is mediated by the recruitment of TRAF/cIAP complexes. Altogether, these results suggest that TRAF/cIAP can be considered as a target for anti-cancer therapies.
  • 12.

    【2hr】Type Iγ phosphatidylinositol phosphate kinase dependent cell migration and invasion are dispensable for tumor metastasis

    包量

    机译 Iγ型磷脂酰肌醇磷酸激酶依赖性细胞迁移和侵袭对于肿瘤转移是必不可少的
    摘要：Type Iγ phosphatidylinositol phosphate kinase (PIPKIγ) has been associated with poor prognosis in breast cancer patients by promoting metastasis. Among the six alternative-splicing isoforms of PIPKIγ, PIPKIγ_i2 specifically targets to focal adhesions and regulates focal adhesion turnover, thus was proposed responsible for tumor metastasis. In the present study, we specifically depleted PIPKIγ_i2 from mouse triple negative breast cancer (TNBC) 4T1 cells and analyzed their behaviors. As expected, PIPKIγ_i2-depleted 4T1 cells exhibited reduced proliferation, migration, and invasion in vitro at a comparable level as pan-PIPKIγ depleted cells. However, PIPKIγ_i2 depletion had no effect on metastasis and progression of 4T1 tumors in vivo. PIPKIγ_i2-depleted tumors showed similar levels of growth, hypoxia state, macrophage infiltration, and angiogenesis as parental tumors, although the pan-PIPKIγ depletion led to substantial inhibition on these aspects. Further investigation revealed that depleting PIPKIγ_i2 alone, unlike depleting all PIPKIγ isoforms, had no effect on PD-L1 expression, the status of the epithelial-to-mesenchymal transition, and the anchorage-independent growth of 4T1 cells. In human TNBC MDA-MB-231 cells, we obtained similar results. Thus, while PIPKIγ_i2 indeed is required for cell migration and invasion, these characteristics are not decisive for metastasis. Other PIPKIγ isoform(s) that regulate the expression of key factors to support cell survival under stresses is more critical for the malignant progression of TNBCs.
  • 13.

    【2hr】Stabilization of PTGES by deubiquitinase USP9X promotes metastatic features of lung cancer via PGE2 signaling

    包量

    机译 去泛素酶USP9X稳定PTGES可通过PGE2信号传导促进肺癌的转移特征
    摘要：Early metastasis and local recurrence are the major causes of mortality and poor prognosis of non-small cell lung cancer (NSCLC). However, the underlying mechanisms of these processes are poorly understood. In this study, we aimed to investigate the roles of the PTGES/PGE2 pathway in lung cancer progression. We found that prostaglandin E synthase (PTGES), a key enzyme for PGE2 synthesis in the arachidonic acid pathway, was highly dysregulated in NSCLC. Dysregulated PTGES was essential for the promotion of tumor migration and metastasis of NSCLC cells. Knockdown of PTGES in lung cancer cells resulted in suppressed cell migration, which was reversed by exogenous PGE2. Consistent with this, PTGES knockdown also reduced the expression of CSC markers, tumor sphere formation, colony forming activity, tumorigenicity, and lung metastasis in vivo. Dysregulated PTGES is mainly attributed to protein stabilization by USP9X, a deubiquitination enzyme. USP9X physically interacted with PTGES and prevented it from proteasome-directed degradation via deubiquitination. Consistent with this, USP9X expression was highly correlated with PTGES expression in NSCLC tumor tissues. Taken together, our results show that the upregulated USP9X-PTGES-PGE2 axis contributes significantly to the metastatic features of NSCLC.
  • 14.

    【2hr】High expression of herpes virus entry mediator is associated with poor prognosis in clear cell renal cell carcinoma

    包量

    机译 疱疹病毒进入介质的高表达与透明细胞肾细胞癌的预后不良有关
    摘要：Herpes virus entry mediator (HVEM), also called tumor necrosis factor receptor superfamily 14 (TNFRSF14), is highly expressed in various tumor tissues and plays critical roles in tumor biology. However, the role of HVEM in clear cell renal cell carcinoma (ccRCC) is unknown. This study evaluated the clinical importance of HVEM in patients with ccRCC. HVEM expression was assessed in fresh and 140 archived paraffin-embedded ccRCC tissue samples by quantitative RT-PCR, western blot, and immunohistochemical staining. HVEM expression was higher in ccRCC than in paired peritumor tissue. Kaplan-Meier analysis showed that high level of HVEM expression was associated with poor overall survival (OS) and disease-free survival (DFS) in patients with ccRCC (both P < 0.001). Multivariate analysis indicated that HVEM overexpression was independently prognostic of survival in ccRCC patients. Two novel nomogram systems were constructed by integrating HVEM expression and other clinical parameters to predict OS (c-index 0.75) and DFS (c-index 0.74) in these patients, with both having better predictive accuracy than traditional TNM (c-index 0.65 for OS and 0.639 for DFS) and Fuhrman (c-index 0.612 for OS and 0.641 for DFS) systems. In addition, HVEM silencing led to an observable reduction in tumor cells growth in vitro and in vivo. Taken together, these findings indicate that high HVEM expression is a novel and independent adverse predictor of clinical outcomes in patients with ccRCC and that HVEM may be a potential therapeutic target.
  • 15.

    【2hr】Temozolomide promotes immune escape of GBM cells via upregulating PD-L1

    包量

    机译 替莫唑胺通过上调PD-L1促进GBM细胞的免疫逃逸
    摘要：Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor with poor prognosis, and currently effective therapeutic strategies are still limited. Although temozolomide (TMZ) is commonly used for GBM therapy and its mechanism was well characterized, while its side effects were required comprehensive investigation. In the present study, we revealed that TMZ-challenged GBM cells strongly suppressed pro-inflammatory cytokines expression in activated periphery blood mononuclear cells (PBMC), which depended on enhanced transcription of CD274 (encoding PD-L1), but not other immune checkpoints, such as CD276, HVEM and galectin-9. Moreover, abundance of membranous PD-L1 was also increased in TMZ-treated GBM cells. When PD-L1 expression was knocked down by short hairpin RNA (shRNA), inhibitory effect of TMZ-treated GBM cells on PBMC became weakened, suggesting that PD-L1 was crucial for immune inhibition capacity of TMZ-treated GBM cells. Additionally, actinomycin D reduced PD-L1 expression in GBM cells after TMZ challenge, indicating that PD-L1 induction occurred at transcriptional level. The immunoblotting results demonstrated that STAT3 signaling was involved in TMZ-mediated PD-L1 induction, and attenuated expression of PD-L1 was observed using STAT3 inhibitor VI or STAT3 shRNA. Finally, the animal study showed that combination of TMZ and PD-1 antibody therapy strongly inhibited tumor growth and achieved the improved survival rate of GBM mice. Accordingly, this study revealed the classical chemotherapy drug TMZ promoted GBM cells immune escape, even TMZ combine with PD-1 antibody treatment not further improve survival ratio of recurrent GBM patients compared with traditional therapy methods, while our animal study provided evidence that combination of TMZ and PD-1 antibody was a promising way to treat GBM, these contradictory results indicate improving the PD-1 antibody delivery efficiency can exert strong combinational therapy outcomes.
  • 16.

    【2hr】Capsaicin attenuates cell migration via SIRT1 targeting and inhibition to enhance cortactin and β-catenin acetylation in bladder cancer cells

    包量

    机译 辣椒素通过SIRT1靶向和抑制作用来减弱细胞迁移，从而增强膀胱癌细胞中的cortactin和β-catenin乙酰化
    摘要：We have studied the chemopreventive property of capsaicin, a major active component in chili pepper, and found that it exhibited apoptotic activity against various lines of cancer cells. Interestingly, accumulating data has revealed that, in addition to cytotoxicity, capsaicin also plays regulatory role on cell migration and invasion. However, its effect on cell migration is paradoxical and not completely understood. Here, we set out to elucidate the molecular events underlying capsaicin-inhibited cell migration in bladder cancer cells. Our results show that the capsaicin-reduced cell migration was associated with down-regulation of sirtuin 1 (SIRT1) deacetylase, possibly through proteasome-mediated protein degradation. More importantly, we employed a cellular thermal shift assay (CETSA) to demonstrate that there was a direct binding between capsaicin and SIRT1. The engagement with capsaicin and protein degradation diminished the deacetylase of SIRT1, which in turn, enhanced acetylation of cortactin and β-catenin to decrease MMP-2 and MMP-9 activation, resulting in cell migration impairment in bladder cancer cells.
  • 17.

    【2hr】Loss of ZNF587B and SULF1 contributed to cisplatin resistance in ovarian cancer cell lines based on Genome-scale CRISPR/Cas9 screening

    包量

    机译 基于基因组规模的CRISPR / Cas9筛选，ZNF587B和SULF1的缺失有助于卵巢癌细胞系中顺铂耐药
    摘要：Ovarian cancer is one of the most lethal malignancies of the female reproductive system. Platinum-resistance is the major obstacle in the successful treatment of ovarian cancer. Previous studies largely failed to identify the key genes associated with platinum-resistance by using candidate genes testing, bioinformatic analysis and GWAS method. The aim of the study was to utilize the whole human Genome-scale CRISPR-Cas9 knockout (GeCKO) library to screen for novel genes involved in cisplatin resistance in ovarian cancer cell lines. The GeCKO library targeted 19052 genes with 122417 unique guide sequences. Six candidate genes had been screened out including one previously validated gene SULF1 and five novel genes ZNF587B, TADA1, SEMA4G, POTEC and USP17L20. After validated by CCK-8 and RT-PCR analysis, two genes (ZNF587B and SULF1) were discovered to be involved in cisplatin resistance. ZNF587B may serve as a new biomarker for predicting cisplatin resistance.
  • 18.

    【2hr】Genome-scale CRISPR activation screening identifies a role of ELAVL2-CDKN1A axis in paclitaxel resistance in esophageal squamous cell carcinoma

    包量

    机译 基因组规模的CRISPR激活筛选确定了食管鳞状细胞癌中ELAVL2-CDKN1A轴在紫杉醇耐药性中的作用
    摘要：Neoadjuvant chemotherapy (NAC) may provide survival benefits for patients with advanced esophageal squamous cell carcinoma. However, tumor cells can display primary or secondary resistance to paclitaxel (PTX), a primary component of induction chemotherapy regimen. To identify genes capable of conveying PTX resistance, we performed a genome-wide CRISPR transcriptional activation library in human KYSE-180 cells. High throughput next generation sequencing was further applied to establish the phenotype-to-genotype relationship. Our highest-ranking hits are CDKN1A, TSPAN4, ELAVL2, JUNB and PAAF1. We generated evidence that esophageal tumors with high CDKN1A, ELAVL2 and TSPAN4 levels, quantified using qRT-PCR and Western blot assays, showed poorer chemotherapy response. Higher expression levels of TSPAN4 and ELAVL2 protein are independent risk factors for poor chemotherapy response in ESCC patients. We then found that overexpression of CDKN1A, ELAVL2 or TSPAN4 in ESCC cell lines significantly promoted the resistance to PTX by inhibiting cell apoptosis. Interestingly, ESCC cells overexpressed CDKN1A, ELAVL2 or TSPAN4 also acquired resistance to cisplatin (DDP). This phenomenon may be explained by cross-resistance of chemotherapy. We additionally found an association between ELAVL2 and CDKN1A, which may be regarded as the upstream and downstream factors that synergistically involved in the regulation of chemo-resistance in ESCC. Therefore, our study demonstrated that the genome-wide CRISPR activation library is a powerful strategy for the discovery of chemo-resistant genes critical for ESCC and we reported the first evidence that the ELAVL2-CDKN1A axis may be an important mechanism involved in chemo-resistance in ESCC.
  • 19.

    【2hr】Aberrant shuttling of long noncoding RNAs during the mitochondria-nuclear crosstalk in hepatocellular carcinoma cells

    包量

    机译 肝癌细胞线粒体-核串扰期间长非编码RNA的异常穿梭。
    摘要：There is intense crosstalk between mitochondria and the nucleus that is mediated by proteins and long noncoding RNAs (lncRNAs). Using a modified RNA fluorescent in situ hybridization (RNA-FISH) assay coupled with MitoTracker staining, we tracked the mitochondrial localization of lncRNAs, including lncND6 and lncCytB. The nuclear genome-transcribed lncRNA MALAT1 was enriched in the mitochondria of hepatocellular carcinoma cells. Knockdown of MALAT1 significantly impaired mitochondrial function and alter tumor phenotype in HepG2 cells. The localization of the mitochondria-encoded lncRNA lncCytB was also abnormal in HepG2 cells. In normal hepatic HL7702 cells, lncCytB was located in mitochondria, but in HepG2 cells, it was enriched considerably in the nucleus. These data suggest that aberrant shuttling of lncRNAs, whether nuclear genome-encoded or mitochondrial genome-transcribed, may play a critical role in abnormal mitochondrial metabolism in cancer cells. This data lays the foundation for further clarifying the roles of mitochondria-associated lncRNAs in cancers.
  • 20.

    【2hr】Glutathione reductase (GSR) gene deletion and chromosome 8 aneuploidy in primary lung cancers detected by fluorescence in situ hybridization

    包量

    机译 荧光原位杂交技术检测原发性肺癌中谷胱甘肽还原酶（GSR）基因的缺失和8号染色体非整倍性
    摘要：Our recent study demonstrated that cancer cells with compromised glutathione homeostasis, including reduced expression of the glutathione reductase (GSR) gene, were selectively killed by inhibition of thioredoxin reductase. The human GSR gene is located on chromosome 8p, a region often lost in lung and other cancers. However, whether GSR is altered in primary lung cancer remains unknown. To analyze alterations of GSR in lung cancer, we performed fluorescence in situ hybridization with probes for GSR and the chromosome 8 centromere (CEP8) in 45 surgical specimens of primary lung cancer, including 24 lung adenocarcinomas, 10 squamous cell carcinomas, 8 neuroendocrine cancers, and 3 small cell lung cancers. Twenty-five surgically resected normal lung tissue specimens from these lung cancer patients were used as a controls. The signal ratio of GSR to CEP8 per cell was used to identify gain or loss of GSR. GSR loss was detected in 6 of 24 (25%) adenocarcinoma specimens and 5 of 10 (50%) squamous cell carcinoma specimens, but not in neuroendocrine cancer or small cell lung cancer specimens. We also found that 19 of 45 (42%) specimens had chromosome 8 aneuploidy (more or less than 2 signals for CEP8), including 8 with both aneuploidy and GSR deletion. Chromosome 8 aneuploidy was detected in all types of lung cancer analyzed. Univariate and multivariable logistic regression analyses indicated that male patients had an increased risk of GSR deletion (hazard ratio [HR] = 4.77, 95% confidence interval [CI] = 1.00-22.86, P = 0.051), and patients who had undergone preoperative radiation therapy or had a self-reported history of cigarette smoking had an increased risk of chromosome 8 aneuploidy (preoperative radiation: HR = 18.63, 95% CI = 0.90-384.17, P = 0.058; smoking: HR = 7.59, 95% CI = 0.86-66.75, P = 0.068), although the p values did not reach significance. Because GSR deficiency and chromosome 8 aneuploidy have implications in targeted therapy and/or immunotherapy for cancer, they might serve as predictive biomarkers for precision therapy of lung cancers.
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