Abstract
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.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide [1, 2]
The monoclonal shAnxa11-hepatocarcinoma ascites cell P (Hca-P) and scramble-Hca-P cells were obtained by limited dilution against G418 screening. Quantitative real-time PCR (qRT-PCR) and western blotting (WB) showed Axna11 mRNA and ANXA11 protein levels were decreased by 82.49±3.49% (P
No statistical significant difference was determined for the expression levels of poly adeno ribose polymerase (PARP) and cleaved PARP in Hca-P cells following the knockdown of ANXA11 (Figure 2B)
Summary
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide [1, 2]. The lymphatic metastasis and chemoresistance are the major problems leading to its high recurrence with low post-surgical 5-years’ survival [3,4,5]. Tumor metastasis is a multistep process, including the invasion of extracellular matrix (ECM), intravasation, translocation, migration and invasion of a secondary site, and the formation of metastatic nodules [3,5]. Annexin A11 (Anxa11) is one member of annexins that are Ca2+-regulated phospholipid-binding proteins [6,7,8,9,10]. The C-terminus of Anxa contains homologous tetrad annexin repeat core with Ca2+ binding sites. The N-terminus of Anxa is rich in glycine, tyrosine and proline residues with calcyclin (S100A6) and apoptosis-linked gene-2 protein (ALG-2) binding www.impactjournals.com/oncotarget sites [11,12,13]. Anxa dysregulation is involved in the progression, drug-resistance, recurrence of systemic autoimmune disease and cancer [14,15,16,17,18]
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