Liver cancer is a prevalent malignant cancer,ranking third in terms of mortality rate.Metastasis and recurrence primarily contribute to the high mortality rate of liver cancer.Hepatocellular carcinoma(HCC)has low expr...Liver cancer is a prevalent malignant cancer,ranking third in terms of mortality rate.Metastasis and recurrence primarily contribute to the high mortality rate of liver cancer.Hepatocellular carcinoma(HCC)has low expression of focal adhesion kinase(FAK),which increases the risk of metastasis and recurrence.Nevertheless,the efficacy of FAK phosphorylation inhibitors is currently limited.Thus,investigating the mechanisms by which FAK affects HCC metastasis to develop targeted therapies for FAK may present a novel strategy to inhibit HCC metastasis.This study examined the correlation between FAK expression and the prognosis of HCC.Additionally,we explored the impact of FAK degradation on HCC metastasis through wound healing experiments,transwell invasion experiments,and a xenograft tumor model.The expression of proteins related to epithelial-mesenchymal transition(EMT)was measured to elucidate the underlying mechanisms.The results showed that FAK PROTAC can degrade FAK,inhibit the migration and invasion of HCC cells in vitro,and notably decrease the lung metastasis of HCC in vivo.Increased expression of E-cadherin and decreased expression of vimentin indicated that EMT was inhibited.Consequently,degradation of FAK through FAK PROTAC effectively suppressed liver cancer metastasis,holding significant clinical implications for treating liver cancer and developing innovative anti-neoplastic drugs.展开更多
目的:研究粘着斑激酶(focal adhesion kinase,FAK)、磷酸化粘着斑激酶(phospho-FAK,Y397)、与张力蛋白同源的第10号染色体丢失的磷酸酶基因(phosphatase and tensinhomolog deleted on chromosome,PTEN)在胃腺癌及癌旁组织中的表达及其...目的:研究粘着斑激酶(focal adhesion kinase,FAK)、磷酸化粘着斑激酶(phospho-FAK,Y397)、与张力蛋白同源的第10号染色体丢失的磷酸酶基因(phosphatase and tensinhomolog deleted on chromosome,PTEN)在胃腺癌及癌旁组织中的表达及其临床意义。方法:采用免疫组织化学S-P法检测FAK、p-FAK(Y397)和PTEN在100例胃腺癌和30例癌旁组织中的表达。结果:胃腺癌与癌旁组织FAK阳性表达率分别为71%(71/100)、43%(13/30)(P<0.05);P-FAK(Y397)阳性表达率分别为62%(62/100)、20%(6/30)(P<0.05);PTEN阳性表达率分别为53%(53/100)、97%(29/30)(P<0.05);癌组织中FAK、p-FAK(Y397)、PTEN的表达与胃腺癌分化程度、浸润深度、淋巴结转移及TNM分期有关(P<0.05),与年龄、性别无关(P>0.05);PTEN与FAK、P-FAK(Y397)在胃腺癌中的表达呈负相关(r=-0.514,-0.572;P<0.05),FAK与p-FAK(Y397)呈正相关(r=0.539;P<0.05)。结论:胃腺癌中存在FAK和p-FAK(Y397)表达上调,PTEN表达下调,三者的表达水平可能与胃腺癌的发生、发展有关。展开更多
目的观察化痰消瘀方对胃癌前病变大鼠PTEN、FAK及paxillin表达的影响,从分子生物学水平探讨其逆转胃癌前病变的作用机制。方法选择90只4~5周龄SD雄性大鼠,随机取15只作为空白组,其余大鼠均采用N-甲基-N’-硝基N-亚硝基胍综合饥饱失常、...目的观察化痰消瘀方对胃癌前病变大鼠PTEN、FAK及paxillin表达的影响,从分子生物学水平探讨其逆转胃癌前病变的作用机制。方法选择90只4~5周龄SD雄性大鼠,随机取15只作为空白组,其余大鼠均采用N-甲基-N’-硝基N-亚硝基胍综合饥饱失常、浓盐水灌胃的方法制备胃癌前病变大鼠模型。将造模成功大鼠随机分为模型组,中药高、中、低剂量组及维酶素组,每组13只。空白组正常饮食,余均造模成功后,模型组给予生理盐水灌胃,中药高、中、低剂量组分别给予3 m L/kg、2 m L/kg、1 m L/kg化痰消瘀方灌胃,维酶素组给予10 m L/kg维酶素灌胃,均灌胃8周。采用HE染色法观察大鼠胃黏膜病理改变情况,应用免疫组化法检测胃黏膜组织中PTEN、FAK及paxillin的表达情况。结果 HE染色显示空白组大鼠胃黏膜无癌前病变改变,模型组均出现不同程度的胃癌前病变改变,中药高、中剂量组和维酶素组胃黏膜癌前病变情况均较模型组明显改善（P均〈0.05）,且中药高剂量组改善程度高于其他各给药组（P均〈0.05）。免疫组化结果显示PTEN在空白组强阳性表达;模型组鲜有表达;中药高、中、低剂量组表达量逐渐降低,但高于模型组（P均〈0.05）;中药高剂量组PTEN表达量高于其他各给药组（P均〈0.05）。FAK、paxillin在空白组极少表达,模型组表达量较空白组显著增加（P均〈0.05）;中药高、中、低剂量组二者表达量均明显低于模型组（P均〈0.05）,其中高剂量组表达量明显低于其他各给药组（P均〈0.05）。结论中药化痰消瘀方可显著改善胃癌前病变大鼠胃黏膜组织病理学情况,其作用机制可能是激活抑癌基因PTEN,调节FAK的去磷酸化,通过FAK/Src信号通路下调paxillin来诱导细胞凋亡。展开更多
基金supported by the National Natural Science Foundation of China Fund Project(82272956).
文摘Liver cancer is a prevalent malignant cancer,ranking third in terms of mortality rate.Metastasis and recurrence primarily contribute to the high mortality rate of liver cancer.Hepatocellular carcinoma(HCC)has low expression of focal adhesion kinase(FAK),which increases the risk of metastasis and recurrence.Nevertheless,the efficacy of FAK phosphorylation inhibitors is currently limited.Thus,investigating the mechanisms by which FAK affects HCC metastasis to develop targeted therapies for FAK may present a novel strategy to inhibit HCC metastasis.This study examined the correlation between FAK expression and the prognosis of HCC.Additionally,we explored the impact of FAK degradation on HCC metastasis through wound healing experiments,transwell invasion experiments,and a xenograft tumor model.The expression of proteins related to epithelial-mesenchymal transition(EMT)was measured to elucidate the underlying mechanisms.The results showed that FAK PROTAC can degrade FAK,inhibit the migration and invasion of HCC cells in vitro,and notably decrease the lung metastasis of HCC in vivo.Increased expression of E-cadherin and decreased expression of vimentin indicated that EMT was inhibited.Consequently,degradation of FAK through FAK PROTAC effectively suppressed liver cancer metastasis,holding significant clinical implications for treating liver cancer and developing innovative anti-neoplastic drugs.
文摘目的探究FAK/Twist1信号通路在颅缝闭合过程中的作用。方法将10 d大鼠分为对照组(50只)和颅缝旋转组(50只),以大鼠人字缝中点为中心,直径约0.5 cm做一骨窗,将骨瓣在不损伤硬脑膜的情况下游离,对照组骨瓣原位复位,旋转组骨瓣旋转180°后复位,两组大鼠3周后进行实验。旷场试验测试行为学,测量两组体质量、头围、骨瓣面积、骨瓣厚度等生理学指标,显微镜及HE染色观察颅缝闭合情况,Western blot、Real time PCR、免疫组化染色测定骨瓣及骨瓣下硬脑膜FAK/Twist1通过表达情况。结果旋转组骨瓣厚度大于对照组,差异有统计学意义(P<0.01),头围、体质量、骨瓣面积、术区面积无明显差异;显微镜下及HE染色中结果显示:旋转组颅缝完全闭合,对照组颅缝保持正常形态;行为学试验结果显示,颅缝闭合后大鼠行动能力下降且出现抑郁倾向;Western blot、Real time PCR、免疫组化染色显示:旋转组FAK在颅骨和硬脑膜中表达量均高于对照组且差异有统计学意义(P<0.05),旋转组Twist1在硬脑膜中表达量低于对照组且差异有统计学意义(P<0.05),在颅骨中两组Twist1表达量相近,差异无统计学意义。结论颅缝旋转后可以导致颅缝早闭,并会出现行动能力下降等行为学异常,FAK/Twist1可能在颅缝闭合过程中发挥着重要作用。
文摘目的:研究粘着斑激酶(focal adhesion kinase,FAK)、磷酸化粘着斑激酶(phospho-FAK,Y397)、与张力蛋白同源的第10号染色体丢失的磷酸酶基因(phosphatase and tensinhomolog deleted on chromosome,PTEN)在胃腺癌及癌旁组织中的表达及其临床意义。方法:采用免疫组织化学S-P法检测FAK、p-FAK(Y397)和PTEN在100例胃腺癌和30例癌旁组织中的表达。结果:胃腺癌与癌旁组织FAK阳性表达率分别为71%(71/100)、43%(13/30)(P<0.05);P-FAK(Y397)阳性表达率分别为62%(62/100)、20%(6/30)(P<0.05);PTEN阳性表达率分别为53%(53/100)、97%(29/30)(P<0.05);癌组织中FAK、p-FAK(Y397)、PTEN的表达与胃腺癌分化程度、浸润深度、淋巴结转移及TNM分期有关(P<0.05),与年龄、性别无关(P>0.05);PTEN与FAK、P-FAK(Y397)在胃腺癌中的表达呈负相关(r=-0.514,-0.572;P<0.05),FAK与p-FAK(Y397)呈正相关(r=0.539;P<0.05)。结论:胃腺癌中存在FAK和p-FAK(Y397)表达上调,PTEN表达下调,三者的表达水平可能与胃腺癌的发生、发展有关。
文摘目的观察化痰消瘀方对胃癌前病变大鼠PTEN、FAK及paxillin表达的影响,从分子生物学水平探讨其逆转胃癌前病变的作用机制。方法选择90只4~5周龄SD雄性大鼠,随机取15只作为空白组,其余大鼠均采用N-甲基-N’-硝基N-亚硝基胍综合饥饱失常、浓盐水灌胃的方法制备胃癌前病变大鼠模型。将造模成功大鼠随机分为模型组,中药高、中、低剂量组及维酶素组,每组13只。空白组正常饮食,余均造模成功后,模型组给予生理盐水灌胃,中药高、中、低剂量组分别给予3 m L/kg、2 m L/kg、1 m L/kg化痰消瘀方灌胃,维酶素组给予10 m L/kg维酶素灌胃,均灌胃8周。采用HE染色法观察大鼠胃黏膜病理改变情况,应用免疫组化法检测胃黏膜组织中PTEN、FAK及paxillin的表达情况。结果 HE染色显示空白组大鼠胃黏膜无癌前病变改变,模型组均出现不同程度的胃癌前病变改变,中药高、中剂量组和维酶素组胃黏膜癌前病变情况均较模型组明显改善（P均〈0.05）,且中药高剂量组改善程度高于其他各给药组（P均〈0.05）。免疫组化结果显示PTEN在空白组强阳性表达;模型组鲜有表达;中药高、中、低剂量组表达量逐渐降低,但高于模型组（P均〈0.05）;中药高剂量组PTEN表达量高于其他各给药组（P均〈0.05）。FAK、paxillin在空白组极少表达,模型组表达量较空白组显著增加（P均〈0.05）;中药高、中、低剂量组二者表达量均明显低于模型组（P均〈0.05）,其中高剂量组表达量明显低于其他各给药组（P均〈0.05）。结论中药化痰消瘀方可显著改善胃癌前病变大鼠胃黏膜组织病理学情况,其作用机制可能是激活抑癌基因PTEN,调节FAK的去磷酸化,通过FAK/Src信号通路下调paxillin来诱导细胞凋亡。
