目的观察纤毛内转运蛋白20(intraflagellar transport 20,IFT20)在卵巢良、恶性肿瘤中的表达,探讨其与卵巢癌发生、发展及预后的关系。方法采用免疫组化SP法检测IFT20在157例卵巢肿瘤组织中的表达,其中浆液性囊腺癌52例、黏液性囊腺癌2...目的观察纤毛内转运蛋白20(intraflagellar transport 20,IFT20)在卵巢良、恶性肿瘤中的表达,探讨其与卵巢癌发生、发展及预后的关系。方法采用免疫组化SP法检测IFT20在157例卵巢肿瘤组织中的表达,其中浆液性囊腺癌52例、黏液性囊腺癌22例、子宫内膜样腺癌14例、透明细胞腺癌10例、交界性卵巢肿瘤25例、良性肿瘤18例及正常卵巢组织16例。结果(1)IFT20在卵巢癌组织(76.5%,75/98)和交界性肿瘤组织(32%,8/25)中的阳性率明显高于卵巢良性肿瘤(16.6%,3/18)和正常卵巢组织(12.5%,2/16),组间差异有统计学意义(P<0.05);(2)IFT20蛋白在不同FIGO分期和组织学分级的卵巢癌组织中的表达差异有显著性(P<0.05),随着FIGO分期和组织学分级的升高,且伴有淋巴结转移的卵巢癌组织中IFT20蛋白的表达显著升高;(3)IFT20蛋白表达强弱与患者生存时间呈负相关(P<0.05)。(4)IFT20蛋白表达与卵巢癌患者年龄无关。结论 IFT20蛋白与卵巢癌的发生、浸润和转移相关,在一定程度上可判断卵巢癌恶性程度和评估临床预后,同时为卵巢癌的靶向治疗提供新靶点。展开更多
Infertility represents a significant health concern,with sperm quantity and quality being crucial determinants of male fertility.Oligoasthenoteratozoospermia(OAT)is characterized by reduced sperm motility,lower sperm ...Infertility represents a significant health concern,with sperm quantity and quality being crucial determinants of male fertility.Oligoasthenoteratozoospermia(OAT)is characterized by reduced sperm motility,lower sperm concentration,and morphological abnormalities in sperm heads and flagella.Although variants in several genes have been implicated in OAT,its genetic etiologies and pathogenetic mechanisms remain inadequately understood.In this study,we identified a homozygous nonsense mutation(c.916C>T,p.Arg306*)in the coiled-coil domain containing 146(CCDC146)gene in an infertile male patient with OAT.This mutation resulted in the production of a truncated CCDC146 protein(amino acids 1-305),retaining only two out of five coiled-coil domains.To validate the pathogenicity of the CCDC146 mutation,we generated a mouse model(Ccdc146^(mut/mut))with a similar mutation to that of the patient.Consistently,the Ccdc146mut/mut mice exhibited infertility,characterized by significantly reduced sperm counts,diminished motility,and multiple defects in sperm heads and flagella.Furthermore,the levels of axonemal proteins,including DNAH17,DNAH1,and SPAG6,were significantly reduced in the sperm of Ccdc146^(mut/mut) mice.Additionally,both human and mouse CCDC146 interacted with intraflagellar transport protein 20(IFT20),but this interaction was lost in the mutated versions,leading to the degradation of IFT20.This study identified a novel deleterious homozygous nonsense mutation in CCDC146 that causes male infertility,potentially by disrupting axonemal protein transportation.These findings offer valuable insights for genetic counseling and understanding the mechanisms underlying CCDC146 mutant-associated infertility in human males.展开更多
文摘目的观察纤毛内转运蛋白20(intraflagellar transport 20,IFT20)在卵巢良、恶性肿瘤中的表达,探讨其与卵巢癌发生、发展及预后的关系。方法采用免疫组化SP法检测IFT20在157例卵巢肿瘤组织中的表达,其中浆液性囊腺癌52例、黏液性囊腺癌22例、子宫内膜样腺癌14例、透明细胞腺癌10例、交界性卵巢肿瘤25例、良性肿瘤18例及正常卵巢组织16例。结果(1)IFT20在卵巢癌组织(76.5%,75/98)和交界性肿瘤组织(32%,8/25)中的阳性率明显高于卵巢良性肿瘤(16.6%,3/18)和正常卵巢组织(12.5%,2/16),组间差异有统计学意义(P<0.05);(2)IFT20蛋白在不同FIGO分期和组织学分级的卵巢癌组织中的表达差异有显著性(P<0.05),随着FIGO分期和组织学分级的升高,且伴有淋巴结转移的卵巢癌组织中IFT20蛋白的表达显著升高;(3)IFT20蛋白表达强弱与患者生存时间呈负相关(P<0.05)。(4)IFT20蛋白表达与卵巢癌患者年龄无关。结论 IFT20蛋白与卵巢癌的发生、浸润和转移相关,在一定程度上可判断卵巢癌恶性程度和评估临床预后,同时为卵巢癌的靶向治疗提供新靶点。
基金supported by the National Key Research and Developmental Program of China(2021YFC2700202,2022YFC2702601,2019YFA0802600,2022YFA0806303)National Natural Science Foundation of China(32470915,32000587,32270901,82171601)+1 种基金Global Select Project(DJK-LX-2022010)of the Institute of Health and Medicine,Hefei Comprehensive National Science Center,Joint Fund for New Medicine of USTC(YD9100002034)Scientific Research Foundation for Scholars of the First Affiliated Hospital of USTC(RC2023054)。
文摘Infertility represents a significant health concern,with sperm quantity and quality being crucial determinants of male fertility.Oligoasthenoteratozoospermia(OAT)is characterized by reduced sperm motility,lower sperm concentration,and morphological abnormalities in sperm heads and flagella.Although variants in several genes have been implicated in OAT,its genetic etiologies and pathogenetic mechanisms remain inadequately understood.In this study,we identified a homozygous nonsense mutation(c.916C>T,p.Arg306*)in the coiled-coil domain containing 146(CCDC146)gene in an infertile male patient with OAT.This mutation resulted in the production of a truncated CCDC146 protein(amino acids 1-305),retaining only two out of five coiled-coil domains.To validate the pathogenicity of the CCDC146 mutation,we generated a mouse model(Ccdc146^(mut/mut))with a similar mutation to that of the patient.Consistently,the Ccdc146mut/mut mice exhibited infertility,characterized by significantly reduced sperm counts,diminished motility,and multiple defects in sperm heads and flagella.Furthermore,the levels of axonemal proteins,including DNAH17,DNAH1,and SPAG6,were significantly reduced in the sperm of Ccdc146^(mut/mut) mice.Additionally,both human and mouse CCDC146 interacted with intraflagellar transport protein 20(IFT20),but this interaction was lost in the mutated versions,leading to the degradation of IFT20.This study identified a novel deleterious homozygous nonsense mutation in CCDC146 that causes male infertility,potentially by disrupting axonemal protein transportation.These findings offer valuable insights for genetic counseling and understanding the mechanisms underlying CCDC146 mutant-associated infertility in human males.
