Liu Shuqing, Guo Chunmei, Wang Jiasheng, Wang Bo, Qi Houbao, Sun Ming-Zhong
Department of Biochemistry, Dalian Medical University, Dalian 116044, China.
Department of Biotechnology, Dalian Medical University, Dalian 116044, China.
Oncotarget. 2016 Mar 29;7(13):16297-310. doi: 10.18632/oncotarget.7484.
Annexin A11 (Anxa11) is associated with various cancers. Using a pair of syngeneic murine hepatocarcinoma cells, Hca-P with ~25% and Hca-F with ~75% lymph node metastatic (LNM) potentials, we demonstrated Anxa11 involvement in hepatocarcinoma lymphatic metastasis. Here, ANXA11 acted as a suppressor for the tumorigenicity, LNM and 5-FU resistance of Hca-P via c-Jun. We constructed monoclonal Hca-P cell line with stable ANXA11 knockdown. Although Bax and Bcl-2 levels increased in shRNA-Anxa11-transfected Hca-P, ANXA11 downregulation showed no clear effect on Hca-P apoptosis. ANXA11 downregulation promoted in vitro migration and invasion capacities of Hca-P. In situ adhesion potential of Hca-P cells toward LN was significantly enhanced following ANXA11 downregulation. Consistently, ANXA11 downregulation promoted the in vivo tumor growth and LNM capacities of Hca-P cells. ANXA11 knockdown enhanced the chemoresistance of Hca-P cells specifically toward 5-FU instead of cisplatin. Its downregulation increased c-Jun (pSer73) and decreased c-Jun (pSer243) levels in Hca-P. c-Jun (pSer243) downregulation seemed to be only correlated with ANXA11 knockdown without the connection to 5-FU treatment. Interestingly, compared with scramble-Hca-P cells, the levels of c-Jun and c-Jun (pSer73) in shRNA-Anxa11-Hca-P cells were upregulated in the presences of 0.1 and 1.0 mg/L 5-FU. The levels changes from c-Jun and c-Jun (pSer73) in Hca-P cells showed a more obvious tendency with the combination of ANXA11 knockdown and 5-FU treatment. ANXA11 level regulates LNM and 5-FU resistance of Hca-P via c-Jun pathway. It might play an important role in hepatocarcinoma cell malignancy and be a therapeutic target for hepatocarcinoma.
膜联蛋白A11（Anxa11）与多种癌症相关。利用一对同基因小鼠肝癌细胞，具有约25%淋巴结转移（LNM）潜能的Hca-P细胞和约75%淋巴结转移潜能的Hca-F细胞，我们证明了Anxa11参与肝癌的淋巴转移。在此，ANXA11通过c-Jun对Hca-P细胞的致瘤性、LNM及5-氟尿嘧啶（5-FU）耐药性起抑制作用。我们构建了稳定敲低ANXA11的Hca-P单克隆细胞系。虽然在转染shRNA-Anxa11的Hca-P细胞中Bax和Bcl-2水平升高，但ANXA11下调对Hca-P细胞凋亡无明显影响。ANXA11下调促进了Hca-P细胞的体外迁移和侵袭能力。ANXA11下调后，Hca-P细胞对淋巴结的原位黏附潜能显著增强。同样，ANXA11下调促进了Hca-P细胞在体内的肿瘤生长和LNM能力。敲低ANXA11增强了Hca-P细胞对5-FU而非顺铂的化疗耐药性。其下调增加了Hca-P细胞中c-Jun（pSer73）水平并降低了c-Jun（pSer243）水平。c-Jun（pSer）下调似乎仅与ANXA11敲低相关，与5-FU处理无关。有趣的是，与对照Hca-P细胞相比，在存在0.1和1.0 mg/L 5-FU的情况下，shRNA-Anxa11-Hca-P细胞中c-Jun和c-Jun（pSer73）水平上调。Hca-P细胞中c-Jun和c-Jun（pSer73）的水平变化在ANXA11敲低与5-FU处理联合时表现出更明显的趋势。ANXA11水平通过c-Jun途径调节Hca-P细胞的LNM和5-FU耐药性。它可能在肝癌细胞恶性肿瘤中起重要作用，并且是肝癌的一个治疗靶点。
