缺氧诱导因子-1α与上皮间质转化

缺氧诱导因子-1α（HIF—1α）是一种细胞缺氧应答调控因子,在多种恶性肿瘤中呈高表达。研究表明,HIF-1α在上皮间质转化（EMT）过程中发挥重要作用,它可通过一系列信号通路及作用机制多方面、多层次地调控EMT的发生,参与肿瘤的侵袭和转移。探寻HIF-1α调控EMT相关机制对开发新的、有效的肿瘤治疗方法有重要意义。     

糖基化在肿瘤相关上皮间质转化中的作用

[摘要] 糖基化是生物体内蛋白质的基本修饰方式之一,通过影响蛋白质的折叠、运输和定位,从而参与人体多种生物学功能的调节。研究表明,异常糖基化修饰参与生物体内多种病理生理过程,包括恶性肿瘤和一些炎症性疾病,尤其与肿瘤的转移和侵袭密切相关。而上皮间质转化（epithelial-mesenchymal transition,EMT）指上皮细胞失去紧密连接转化为间质的复杂过程,是肿瘤转移的重要机制之一。本文主要对蛋白质糖。     

黏着斑激酶、整合素α5,β1亚基及转化生长因子β1在人乳腺癌组织中的表达及其意义

目的研究人乳腺癌组织及癌旁组织中黏着斑激酶（FAK），整合素α5，β亚基及转化生长因子β（TGFβ1）中表达的差异性，以及它们与乳腺癌生物学行为的相关性。方法运用免疫组化SP法检测76例乳腺癌和36例癌旁组织FAK，整合素α5，β1亚基及TGFβ1表达的情况。结果76例乳腺癌组织中FAK表达的阳性率为81．58％（62／76），整合素α5为30．48％（23／76），整合素β1为25．00％（19／76），TGFβ1为6579％（50／76）；36例癌旁组织中FAK表达的阳性率为5．56％（2／36），整合素α5为75．00％（27／36），整合素β1为83．33％（30／36），TGFβ1为27．77％（10／36），统计分析发现它们之间差异存在显著差异性（P〈0．01）。FAK与乳腺癌的大小，组织学分级（SBR分级），pTNM分期及腋淋巴结转移有关（P〈0．05或P〈0．01），而与患者年龄，绝经状况，ER，PR，C-erbB-2无关（P〉0．05）。整合素α5，β1与乳腺癌的组织学分级（SBR分级），pTNM分期及腋淋巴结转移有关（P〈0．05），而与患者年龄，肿瘤大小，绝经状况，ER，PR，C—erbB-2无关（P〉0．05）。TGFβ1仅与腋淋巴结转移有关（P〈0．05），而与其他因素无关（P〉0．05）。FAK与整合素α5，β1之间存在负相关（P〈0．05），TGFβ1与FAK之间存在正相关（P〈0．01），而整合素α5，β1与TGFβ1之间无显著相关性（P〉0.05）。结论FAK、整合素α5、β，TGFβ1与乳腺癌增殖、分化、侵袭、转移密切相关，其中整合素α5，β1可能对肿瘤的侵袭转移起负性调控作用，而FAK，TGFβ1可能对肿瘤的侵袭转移起正性调控作用且两者有协同作用。联合检测这4种蛋白的表达有助于了解乳腺癌发生的分子机制，并可作为指导乳腺癌临床诊疗较有参考价值的指标。     

肿瘤内长链非编码RNA HNF1A-AS1的调控作用研究进展

摘 要：研究发现近98%的人类基因组转录本不编码蛋白质而隶属于非编码RNA（non-coding RNA,ncRNA）家族,在这其中长链非编码RNA（long non-coding RNA,LncRNA）是重要的成员之一。起初LncRNA被视为转录过程中的“噪音”,随着研究的深入,发现LncRNA参与调控了人体诸多的生理病理过程。此外,在多种人体恶性肿瘤中证实LncRNA呈现异常表达并调控肿瘤的发生发展。LncRNA HNF1A-AS1在多种恶性肿瘤中呈异常高表达,并能够促进肿瘤的恶性生物学行为,全文就LncRNA HNF1A-AS1在肿瘤中的调控作用研究作一综述。     

COX-2、TGF-β1和HIF-1α表达与乳腺癌侵袭转移的关系

目的：研究乳腺癌组织中环氧化酶-2（COX-2）、转化生长因子（TGF-β1）和缺氧诱导因子1（HIF-1α）表达与肿瘤侵袭转移的关系。方法：应用免疫组织化学SP法检测78例乳腺浸润性导管癌（IDC）、18例乳腺导管内癌（DCIS）和26例乳腺增生组织中COX-2、TGF-β1和HIF-1α的表达情况。结果：IDC中,COX-2、TGF-β1和HIF-1α阳性表达率分别为79.5%、64.1%和57.8%,显著高于DCIS和乳腺增生组织（P〈0.05）。COX-2、TGF-β1、HIF-1α高表达与IDC患者肿瘤大小无关（P〉0.05）,与组织学分级、淋巴结及远处转移呈正相关（P〈0.05）。结论：COX-2、TGF-β1、HIF-1α高表达是乳腺癌侵袭转移行为的重要生物学标志,三项联合检测可作为乳腺癌判断预后的指标以及有可能成为分子靶向治疗的靶点。     

Neuropilin-1在消化道恶性肿瘤发生发展中的生物学作用

消化道肿瘤是最常见的恶性肿瘤,发病率高,死亡率亦高。神经纤毛蛋白-1（Neuropilin-1）在消化道恶性肿瘤发生发展中的作用成为近年来研究的热点,其调控恶性肿瘤血管生成过程,介导肿瘤细胞的增殖与侵袭,从而促进肿瘤进展与转移。本文就Neuropilin-1在肿瘤血管生成、肿瘤增殖与侵袭、转移及肿瘤治疗靶标中的作用作一综述。     

整合素α5β1与肿瘤发生、发展相关性的研究进展

整合素是细胞表面的一种重要粘附分子,在肿瘤的粘附、增殖、分化、转移、凋亡等过程中发挥重要的调控作用。整合素α5β1是整合素家族的重要成员之一,也是纤连蛋白的一个重要受体。整合素α5β1有望成为多种肿瘤诊断、预后预测的重要指标及治疗靶点。本文就整合素α5β1与肿瘤发生、发展的关系作一综述。     

OTUB1在肿瘤中的研究进展

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

β-catenin、STT3A和PD-L1在胃癌组织中的表达及与病理特征和预后的相关性

目的:探讨β-catenin、STT3A及PD-L1相关蛋白在胃癌组织中的表达相关性及其与病理特征和预后相关性。方法:选取2020年02月至 2021年10月63例胃癌组织及癌旁组织蜡块标本,通过免疫组化检测胃癌及癌旁组织中β-catenin、STT3A及PD-L1相关蛋白的表达情况,探讨其与临床病理参数之间的关系,并分析β-catenin、STT3A及PD-L1三者之间的相关性。通过Western blot检测胃癌细胞中的β-catenin、STT3A及PD-L1蛋白的表达情况,探讨稳定PD-L1表达糖基化修饰的可能影响因素,为胃癌免疫检查点抑制剂疗法提供新思路。结果:胃癌组织中β-catenin、STT3A阳性表达率高于癌旁组织（P<0.05）,与肿瘤分化程度、肿瘤直径、淋巴结转移、临床TNM分期有关（P<0.05）,但与年龄、性别均无显著相关性（P>0.05）。胃癌组织中PD-L1阳性表达率高于癌旁组织（P<0.05）,与肿瘤分化程度、临床TNM分期有关（P<0.05）,而与年龄、性别、肿瘤直径、淋巴结转移无显著相关性（P>0.05）。在胃癌组织中,β-catenin与STT3A、PD-L1的表达呈正相关（P<0.05）,PD-L1与STT3A的表达呈正相关（P<0.05）。结论:胃癌组织中β-catenin、STT3A、PD-L1三种蛋白的表达均高于癌旁组织,且与肿瘤分化程度、临床TNM分期有关,因此三种蛋白可能与肿瘤的预后相关。此外,β-catenin、STT3A、PD-L1三者之间的的表达呈相关性,结果表明胃癌组织中可能存在β-catenin调控STT3A从而调节PD-L1的糖基化过程,从而影响PD-L1稳定性的表达。     

乳腺癌标本整合素α5β1基因的表达水平及其临床意义

目的近年来的研究发现整合素对肿瘤的增殖、分化、转移起重要作用。整合素α5β1作为其一亚型证实该基因的低表达和黑素瘤，肠癌等肿瘤的恶性程度，肿瘤转移有关。本研究探讨其在乳腺癌中的作用及临床意义。方法应用Northern杂交和图象分析技术，定量检测了5例乳腺良性病变和17例乳腺癌组织中整合素α5β1基因mRNA的表达水平，结合肿瘤大小，TNM分期和腋下淋巴结转移情况等临床和病理指标进行比较分析。结果（1）乳腺良性病变组整合素α5β1基因mRNA的表达要高于乳腺癌组（P相似文献   

C1GALT1 overexpression promotes the invasive behavior of colon cancer cells through modifying O-glycosylation of FGFR2

Core 1 β1,3-galactosyltransferase (C1GALT1) transfers galactose (Gal) to N-acetylgalactosamine (GalNAc) to form Galβ1,3GalNAc (T antigen). Aberrant O-glycans, such as T antigen, are commonly found in colorectal cancer. However, the role of C1GALT1 in colorectal cancer remains unclear. Here we showed that C1GALT1 was frequently overexpressed in colorectal tumors and is associated with poor survival. C1GALT1 overexpression promoted cell survival, migration, invasion, and sphere formation as well as tumor growth and metastasis of colon cancer cells. Conversely, knockdown of C1GALT1 with small interference (si) RNA was sufficient to suppress these malignant phenotypes in vitro and in vivo. Moreover, we are the first to show that fibroblast growth factor receptor (FGFR) 2 carried O-glycans in colon cancer cells. Mechanistic investigations showed that C1GALT1 modified the O-glycans on FGFR2 and enhanced bFGF-triggered activation of FGFR2 as well as increased bFGF-mediated malignant phenotypes. In addition, BGJ398, a selective inhibitor of FGFR, blocked the effects of C1GALT1. These findings suggest that C1GALT1 overexpression modifies O-glycans on FGFR2 and enhances its phosphorylation to promote the invasive behavior and cancer stem-like property in colon cancer cells, indicating a critical role of O-glycosylation in the pathogenesis of colorectal cancer.     

Up-regulation of C1GALT1 promotes breast cancer cell growth through MUC1-C signaling pathway

Aberrant glycosylation is frequently observed in cancers. Core 1 β1,3-galactosyltransferase (C1GALT1) is an exclusive enzyme in humans that catalyzes the biosynthesis of core 1 O-glycan structure, Gal-GalNAc-O-Ser/Thr, whose expression is commonly up-regulated during tumorigenesis. Little is known about the function of C1GALT1 in breast cancer. This study aims to determine the correlation between C1GALT1 expression and breast cancer clinicopathological features and roles of C1GALT1 in breast cancer malignant phenotypes. Public databases and our data showed that C1GALT1 mRNA and C1GALT1 protein are frequently up-regulated in breast cancer; and increased C1GALT1 expression correlates with higher histological grade and advanced tumor stage. Overexpression of C1GALT1 enhanced breast cancer cell growth, migration, and invasion in vitro as well as tumor growth in vivo. Conversely, C1GALT1 knockdown suppressed these malignant phenotypes. Furthermore, C1GALT1 modulates O-glycan structures on Mucin (MUC) 1 and promotes MUC1-C/β-catenin signaling in breast cancer cells. These findings suggest that C1GALT1 enhances breast cancer malignant progression through promoting MUC1-C/β-catenin signaling pathway. Unveiling the function of C1GALT1 in breast cancer opens new insights to the roles of C1GALT1 and O-glycosylation in tumorigenesis and renders the potential of C1GALT1 as a target of novel therapeutic agent development.     

C1GALT1 in health and disease

O-linked glycosylation (O-glycosylation) and N-linked glycosylation (N-glycosylation) are the two most important forms of protein glycosylation, which is an important post-translational modification. The regulation of protein function involves numerous mechanisms, among which protein glycosylation is one of the most important. Core 1 synthase glycoprotein-N-acetylgalactosamine 3-β-galactosyltransferase 1 (C1GALT1) serves an important role in the regulation of O-glycosylation and is an essential enzyme for synthesizing the core 1 structure of mucin-type O-glycans. Furthermore, C1GALT1 serves a vital role in a number of biological functions, such as angiogenesis, platelet production and kidney development. Impaired C1GALT1 expression activity has been associated with different types of human diseases, including inflammatory or immune-mediated diseases, and cancer. O-glycosylation exists in normal tissues, as well as in tumor tissues. Previous studies have revealed that changes in the level of glycosyltransferase in different types of cancer may be used as potential therapeutic targets. Currently, numerous studies have reported the dual role of C1GALT1 in tumors (carcinogenesis and cancer suppression). The present review reports the role of C1GALT1 in normal development and human diseases. Since the mechanism and regulation of C1GALT1 and O-glycosylation remain elusive, further studies are required to elucidate their effects on development and disease.     

Serum antiglycan antibody detection of nonmucinous ovarian cancers by using a printed glycan array

Epithelial ovarian cancer has the highest mortality rate among gynecological cancers. Altered glycosylation is associated with oncogenic transformation producing tumor-associated carbohydrate antigens. We investigated the potential of natural occurring antiglycan antibodies in the diagnosis of ovarian cancer by using printed glycan array. Antiglycan antibodies bound to 203 chemically synthesized printed glycans were detected via biotin-streptavidin fluorescence system in serum of women with normal operative findings (healthy controls; n = 24) and nonmucinous borderline or ovarian cancer of various FIGO stages (n = 33). Data were validated measuring blood group associated di-, tri and tetrasaccharide antigens on known ABO blood groups. Antiglycan antibodies demonstrated high reproducibility (r(c) > 0.9). Cluster analysis identified repetitive patterns of specific core carbohydrate structures: 11 N-linked glycans, 3 O-linked glycans and 2 glycosphingolipids. Biomarker detection revealed 24 glycans including P(1) (Galα1-4Galβ1-4GlcNAcβ; p < 0.001) significantly discriminating between (low-) malignant tumors and healthy controls. Comparable sensitivity and specificity with tumor marker CA125 was achieved by a panel of multivariate selected and linear combined antiglycan antibody signals (79.2 and 84.8%, respectively). Our findings demonstrate the potential of glycan arrays in the development of a new generation of biomarkers for ovarian cancer.     

Tumor suppressor KIF1Bβ regulates mitochondrial apoptosis in collaboration with YME1L1

KIF1Bβ, a member of the kinesin superfamily of motor proteins, is a haploinsufficient tumor suppressor mapped to chromosome 1p36.2, which is frequently deleted in neural crest–derived tumors, including neuroblastoma and pheochromocytoma. While KIF1Bβ acts downstream of the nerve growth factor (NGF) pathway to induce apoptosis, further molecular functions of this gene product have largely been unexplored. In this study, we report that KIF1Bβ destabilizes the morphological structure of mitochondria, which is critical for cell survival and apoptosis. We identified YME1L1, a mitochondrial metalloprotease responsible for the cleavage of the mitochondrial GTPase OPA1, as a physical interacting partner of KIF1Bβ. KIF1Bβ interacted with YME1L1 through its death‐inducing region, as initiated the protease activity of YME1L1 to cleave the long forms of OPA1, resulting in mitochondrial fragmentation. Overexpression of YME1L1 promoted apoptosis, while knockdown of YME1L1 promoted cell growth. High YME1L1 expression was significantly associated with a better prognosis in neuroblastoma. Furthermore, in NGF‐deprived PC12 cells, KIF1Bβ and YME1L1 were upregulated, accompanied by mitochondrial fragmentation and apoptotic cell death. Small interfering RNA–mediated knockdown of either protein alone, however, remarkably inhibited the NGF depletion–induced apoptosis. Our findings indicate that tumor suppressor KIF1Bβ plays an important role in intrinsic mitochondria–mediated apoptosis through the regulation of structural and functional dynamics of mitochondria in collaboration with YME1L1. Dysfunction of the KIF1Bβ/YME1L1/OPA1 mechanism may be involved in malignant biological features of neural crest–derived tumors as well as the initiation and progression of neurodegenerative diseases.     

Changes in expression of human serine protease HtrA1, HtrA2 and HtrA3 genes in benign and malignant thyroid tumors

Human HtrA proteins are serine proteases involved in essential physiological processes. HtrA1 and HtrA3 function as tumor suppressors and inhibitors of the TGF-β signaling pathway. HtrA2 regulates mitochondrial homeostasis and plays a pivotal role in the induction of apoptosis. The aim of the study was to determine whether the HtrA proteins are involved in thyroid carcinogenesis. We used the immunoblotting technique to estimate protein levels of HtrA1, HtrA2, long and short variants of HtrA3 (HtrA3-L and HtrA3-S) and TGF-β1 in tissues of benign and malignant thyroid lesions, and control groups. We found that the levels of HtrA2 and HtrA3-S were higher in thyroid malignant tumors compared to normal tissues and benign tumors. The HtrA3-L level was increased in malignant tumor tissues compared to benign tumor tissues and control tissues from patients with benign lesions, and elevated in normal tissues from patients with thyroid carcinoma compared to normal tissues from patients with benign lesions. We also compared levels of HtrA proteins in follicular thyroid carcinoma (FTC) and papillary thyroid carcinoma (PTC) and found that these types of carcinoma differed in the expression of HtrA3-S and HtrA1. These results indicate the implication of HtrA proteins in thyroid carcinogenesis suggest that HtrA3 variants may play different roles in cancer development, and that the increased HtrA3-L levels in thyroid tissue could be correlated with the development of malignant lesions. The TGF-β1 levels in tumor tissues were not significantly altered compared to control tissues.     

Sialylated core 1 based O-linked glycans enhance the growth rate of mammary carcinoma cells in MUC1 transgenic mice

The MUC1 mucin, found on the luminal surface of simple epithelial cells is upregulated and aberrantly glycosylated in many carcinomas particularly breast and ovarian. MUC1 expressed by normal mammary epithelial cells, carries core 2 glycans but in breast carcinomas the simple core 1 based glycans are added. The binding of the monoclonal antibody SM3 to its peptide epitope in the tandem repeat of MUC1 is blocked by the branched core 2 glycans found on MUC1 expressed by normal cells. Thus SM3 does not bind to MUC1 expressed by normal mammary epithelial cells but reacts with more than 90% of breast carcinomas, suggesting that the loss of at least some core 2 glycans is a very common event in breast carcinogenesis. To determine if the change in glycosylation observed in breast carcinomas confers an advantage to cancer cells, murine mammary carcinoma cell lines were developed that express MUC1 carrying core 2 or core 1 linked glycans. The in vivo growth rate in wild-type and nude mice were identical regardless of the O-glycosylation patterns. However, the tumors that grew out of wild-type mice lost most of their MUC1 expression. In contrast, in MUC1 transgenic mice, where expression of MUC1 was retained by the tumor, a striking difference in growth rate was observed. In these mice, cells expressing core 1 glycans grew significantly faster than cells expressing core 2 glycans. These data suggest that MUC1 transgenic mice are more tolerant to core 1 expressing tumors than to tumors expressing core 2.     

Changes in glycosphingolipids accompanying the differentiation of human squamous SQCC/Y1 cells

SqCC/Y1 cells grow as a monolayer in culture and differentiate when maintained in the plateau phase; in the absence of serum these cells differentiate more rapidly. The differentiation is characterized by the stratification of the culture to form a structure consisting of several cellular layers, synthesis of specific keratins, and the attainment of the capacity to form a cornified cell membrane. The stratification process is indicative of the importance of cell-cell interactions during maturation. To study the relationship between membrane glycosphingolipids (GSLs) and the state of differentiation of SqCC/Y1 cells, GSLs were measured in cultures grown in the presence or absence of fetal calf serum. Glycolipids were isolated by diethylaminoethyl-Sephadex and Iatrobeads column chromatographies, and their distributions were determined by high-performance thin-layer chromatography. GM3 was the major ganglioside present in these cells. Other ganglioside components were tentatively identified as GM2, GM1, and GD3. Differences in ganglioside patterns were observed in differentiated cultures; the major changes were accumulation of GD3 and depletion of GM1. The predominant neutral GSLs in SqCC/Y1 cells were identified as Glc beta 1-1Cer, Gal beta 1-4Glc beta 1-1Cer, Gal beta 1-4Gal alpha 1-4Glc beta 1-1Cer, Gal NAc beta 1-3Gal alpha 1-4Gal beta 1-4Glc beta 1-1Cer, and three unknown complex GSLs. Differentiated cultures, however, showed variations in banding patterns, which include an increase in Glc beta 1-1Cer and Gal beta 1-4Glc beta 1-1Cer and a decrease in Gal alpha 1-4Gal beta 1-4Glc beta 1-1Cer and Gal NAc beta 1-3Gal alpha 1-4Gal beta 1-4Glc beta-1Cer. These changes, however, were not observed when the cells were grown in the presence of epidermal growth factor or retinoic acid, factors which inhibit the differentiation process. The findings demonstrate significant changes in glycolipid composition of differentiated SqCC/Y1 cells grown in the absence of serum, suggesting that these lipids may be important to the differentiated state.     

Overexpression of GalNAc-transferase GalNAc-T3 promotes pancreatic cancer cell growth

O-linked glycans of secreted and membrane-bound proteins have an important role in the pathogenesis of pancreatic cancer by modulating immune responses, inflammation and tumorigenesis. A critical aspect of O-glycosylation, the position at which proteins are glycosylated with N-acetyl-galactosamine on serine and threonine residues, is regulated by the substrate specificity of UDP-GalNAc:polypeptide N-acetylgalactosaminyl-transferases (GalNAc-Ts). Thus, GalNAc-Ts regulate the first committed step in O-glycosylated protein biosynthesis, determine sites of O-glycosylation on proteins and are important for understanding normal and carcinoma-associated O-glycosylation. We have found that one of these enzymes, GalNAc-T3, is overexpressed in human pancreatic cancer tissues and suppression of GalNAc-T3 significantly attenuates the growth of pancreatic cancer cells in vitro and in vivo. In addition, suppression of GalNAc-T3 induces apoptosis of pancreatic cancer cells. Our results indicate that GalNAc-T3 is likely involved in pancreatic carcinogenesis. Modification of cellular glycosylation occurs in nearly all types of cancer as a result of alterations in the expression levels of glycosyltransferases. We report guanine the nucleotide-binding protein, α-transducing activity polypeptide-1 (GNAT1) as a possible substrate protein of GalNAc-T3. GalNAc-T3 is associated with O-glycosylation of GNAT1 and affects the subcellular distribution of GNAT1. Knocking down endogenous GNAT1 significantly suppresses the growth/survival of PDAC cells. Our results imply that GalNAc-T3 contributes to the function of O-glycosylated proteins and thereby affects the growth and survival of pancreatic cancer cells. Thus, substrate proteins of GalNAc-T3 should serve as important therapeutic targets for pancreatic cancers.