p62 Overexpression Promotes Bone Metastasis of Lung Adenocarcinoma out of LC3-Dependent Autophagy.
p62 Overexpression Promotes Bone Metastasis of Lung Adenocarcinoma out of LC3-Dependent Autophagy.
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p62 过表达通过 LC3 依赖性自噬促进肺腺癌骨转移。
DOI：
10.3389/fonc.2021.609548
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发表时间：
2021
影响因子：
4.7
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Li D;He C;Ye F;Ye E;He H;Chen G;Zhang J
P62蛋白与骨转移密切相关，是一种与自噬相关的多功能接头蛋白。因此，我们研究了p62在肺腺癌骨转移中的表达及其预后意义，并分析了其机制是否依赖于自噬。采用逆转录定量聚合酶链式反应和蛋白印迹法分别检测6例新鲜骨转移瘤组织和3例正常松质骨组织中p62、LC3B和Beclin 1mRNA和蛋白的表达。用免疫组织化学方法分析62例石蜡包埋的骨转移瘤标本中p62和LC3B的表达与患者预后的关系。利用小干扰RNA(SiRNA)下调SPC-A-1和A549细胞中p62的表达。CCK8法、CCF法和Transwell法分别检测细胞增殖和迁移能力。用雷帕霉素诱导A549细胞自噬，用ATG 7基因敲除/氯喹抑制A549细胞自噬，并分析p62和LC3II/I的表达。裸鼠皮下接种A549细胞或心内注射A549细胞后，通过组织病理学检查分析p62基因在体内的下调作用。结果表明，p62、LC3B和Beclin 1mRNA和蛋白在骨转移瘤组织中均有过表达(P均<0.01)。与p62低表达患者相比，p62高表达患者骨病变更多(P=0.014，P=0.003)，总生存率和无进展生存率更短(P=0.048)。COX回归分析显示，p62表达是骨转移患者总生存期的独立预后指标(P=0.007)。在体外，p62下调可抑制SPC-A-1和A549细胞的迁移，但对细胞增殖无影响。在自噬诱导或抑制后，p62的表达参与了自噬通量，并且在不同的自噬条件下，随着LC3I向LC3II的切换，p62的表达变化不一致。体内p62基因下调对皮下肿瘤生长无影响。所有模型小鼠均未发现肺或骨转移灶。这些结果表明，p62的过表达促进了肿瘤细胞对Lc3依赖的自噬的侵袭，可作为肺腺癌骨转移的潜在预后生物标志物和治疗靶点。
p62 protein has been implicated in bone metastasis and is a multifunctional adaptor protein usually correlated with autophagy. Herein, we investigated p62 expression and its prognostic significance in bone metastasis of lung adenocarcinoma, and analyzed whether the mechanism involved depends on autophagy. mRNA and protein expression of p62, LC3B and Beclin 1 were detected by reverse transcription-quantitative PCR and western blotting, respectively, in fresh bone metastasis tissues (n=6 cases) and normal cancellous bone tissues (n=3 cases). The association between p62 and LC3B expression and patient prognosis was subsequently analyzed in 62 paraffin-embedded bone metastasis specimens by immunohistochemistry assay. Small interfering RNA (siRNA) was employed to downregulate p62 expression in SPC-A-1 and A549 cells. Cell proliferation and migration ability were tested by CCK8, CCF and Transwell assays respectively. Autophagy was induced by Rapamycin or inhibited by Atg 7 knockout/Chloroquine in A549 cells and p62 and LC3II/I expression were analyzed. After subcutaneous inoculation or intracardial injection of A549 cells into nude mice, the effect of p62 downregulation in vivo was analyzed by histopathological examination. The results showed that p62, LC3B and Beclin 1 mRNA and protein were all overexpressed in bone metastasis tissues (all P<0.01). Patient samples with high p62 expression levels were significantly associated with more bone lesions (>3), shorter overall survival rates and shorter progression free survival rates compared with patients having lower p62 expression (P=0.014, P=0.003, P=0.048, respectively). Cox regression analysis identified p62 expression as an independent prognostic indicator of overall survival of patients with bone metastasis (P=0.007). In vitro p62 downregulation inhibited SPC-A-1 and A549 cells migration but had no effect on cell proliferation. After autophagy induction or inhibition, p62 expression involved in autophagy flux and changed inconsistently according to the switch of LC3I to LC3II in different autophagy conditions. In vivo p62 downregulation had no effect on growth of subcutaneous tumor. Lung or bone metastasis lesion was not found in all mice model. These findings suggested that p62 overexpression promotes tumor cell invasion out of LC3-dependent autophagy, which could be used a potential prognostic biomarker and therapeutic target for bone metastasis of lung adenocarcinoma.
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影响因子：
4
作者：
Park HS;Lee DH;Kang DH;Yeo MK;Bae G;Lee D;Yoo G;Kim JO;Moon E;Huh YH;Lee SH;Jo EK;Cho SY;Lee JE;Chung C
通讯作者：
Chung C
影响因子：
--
作者：
Ponomarenko DM;Klimova ID;Chapygina YA;Dvornichenko VV;Zhukova NV;Orlova RV;Manikhas GM;Zyryanov AV;Burkhanova LA;Badrtdinova II;Oshchepkov BN;Filippova EV;Orlov SV;Kolesnikov SI;Sufianov AA;Baum SR;Zaitzeva OY;Komissarov AB;Grudinin MP;Kiselev OI;Tsyb AF;Venanzi F;Shcherbinina V;Chursov A;Gabai VL;Shneider AM
通讯作者：
Shneider AM
[LC-3和p62在非小细胞肺癌中的表达和临床意义]。
DOI：
10.3779/j.issn.1009-3419.2018.06.04
发表时间：
2018-06-20
期刊：
Zhongguo fei ai za zhi = Chinese journal of lung cancer
影响因子：
--
作者：
Wang C;Li Y;Li Y;Gong H;Zhang H;Yuan Y;Li W;Liu H;Chen J
通讯作者：
Chen J
影响因子：
3
作者：
Wu, Qiong;Xiang, Manlin;Yi, Bin
通讯作者：
Yi, Bin
DOI：
10.1083/jcb.201708168
发表时间：
2018-05-07
期刊：
The Journal of cell biology
影响因子：
--
作者：
Sha Z;Schnell HM;Ruoff K;Goldberg A
通讯作者：
Goldberg A