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Downregulation of annexin A3 inhibits tumor metastasis and decreases drug resistance in breast cancer.

ABSTRACT: Annexin A3 (ANXA3) is dysregulated and plays an important role in various cancers. However, the role of ANXA3 in breast cancer is still unclear. Here, we observed that the expression level of ANXA3 was significantly upregulated in breast cancer tissues. ANXA3 knockdown inhibited cell invasion but promoted cell proliferation in both in vitro and in vivo assays. Furthermore, we found that ANXA3 knockdown inhibited the NF?B pathway via upregulating I?B?, resulting in mesenchymal-epithelial transition (MET) and a heterogeneity change of breast cancer stem cells (BCSCs). In addition, we demonstrated that ANXA3 knockdown increased the sensitivity of breast cancer cells to doxorubicin by increasing the drug uptake. The combination of ANXA3 knockdown and doxorubicin treatment simultaneously inhibited tumor growth and metastasis in vivo. This study described the role and mechanisms of ANXA3 in regulating BCSCs and breast cancer growth and metastasis, indicating that downregulating ANXA3 together with chemotherapy might be a novel therapeutic strategy for treating breast cancer.

SUBMITTER: Du R

PROVIDER: S-EPMC5833718 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Downregulation of annexin A3 inhibits tumor metastasis and decreases drug resistance in breast cancer.

Du Ruikai R Liu Bingjie B Zhou Lei L Wang Dong D He Xueyan X Xu Xiaojun X Zhang Lixing L Niu Chaoshi C Liu Suling S

Cell death & disease 20180126 2

Annexin A3 (ANXA3) is dysregulated and plays an important role in various cancers. However, the role of ANXA3 in breast cancer is still unclear. Here, we observed that the expression level of ANXA3 was significantly upregulated in breast cancer tissues. ANXA3 knockdown inhibited cell invasion but promoted cell proliferation in both in vitro and in vivo assays. Furthermore, we found that ANXA3 knockdown inhibited the NFκB pathway via upregulating IκBα, resulting in mesenchymal-epithelial transiti ...[more]

PMID: 29374148

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Project description:Anoikis is a type of apoptosis induced by cell detachment from the extracellular matrix (ECM), which removes mislocalized cells. Acquisition of anoikis resistance is critical for cancer cells to survive during circulation and, thus, metastasize at a secondary site. Although the sensitization of cancer cells to anoikis is a potential strategy to prevent metastasis, the mechanism underlying anoikis resistance is not well defined. Although family with sequence similarity 188 member B (FAM188B) is predicted as a new deubiquitinase (DUB) member, its biological function has not been fully studied. In this study, we demonstrated that FAM188B knockdown sensitized anoikis of lung cancer cell lines expressing WT-EGFR (A549 and H1299) or TKI-resistant EGFR mutant T790M/L858R (H1975). FAM188B knockdown using si-FAM188B inhibited the growth of all three human lung cancer cell lines cultured in both attachment and suspension conditions. FAM188B knockdown resulted in EGFR downregulation and thus decreased its activity. FAM188B knockdown decreased the activities of several oncogenic proteins downstream of EGFR that are involved in anoikis resistance, including pAkt, pSrc, and pSTAT3, with little changes to their protein levels. Intriguingly, si-FAM188B treatment increased EGFR mRNA levels but decreased its protein levels, which was reversed by treatment with the proteasomal inhibitor MG132, indicating that FAM188B regulates EGFR levels via the proteasomal pathway. In addition, cells transfected with si-FAM188B had decreased expression of FOXM1, an oncogenic transcription factor involved in cell growth and survival. Moreover, FAM188B downregulation reduced metastatic characteristics, such as cell adhesion, invasion, and migration, as well as growth in 3D culture conditions. Finally, tail vein injection of si-FAM188B-treated A549 cells resulted in a decrease in lung metastasis and an increase in mice survival in vivo. Taken together, these findings indicate that FAM188B plays an important role in anoikis resistance and metastatic characteristics by maintaining the levels of various oncogenic proteins and/or their activity, leading to tumor malignancy. Our study suggests FAM188B as a potential target for controlling tumor malignancy.

Dataset Information

Downregulation of annexin A3 inhibits tumor metastasis and decreases drug resistance in breast cancer.

Publications

Downregulation of annexin A3 inhibits tumor metastasis and decreases drug resistance in breast cancer.

Similar Datasets

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