br Keywords br Bach br Epithelial ovarian
Epithelial ovarian cancer metastasis
Epithelial-mesenchymal transition (EMT)
Transcriptional factor BTB and CNC homology 1 (Bach1) has been linked to tumor progression and metastasis, but the mechanisms underlying the eﬀects of Bach1 on tumor growth and metastasis are largely uncharacterized. Here, we report that Bach1 expression was significantly higher in human epithelial ovarian cancer (EOC) tissues than in normal ovarian tissues and that higher levels of Bach1 were associated with tumor stage and poorer overall and progression-free survival. We found that Bach1 enhanced the expression of epithelial-mesenchymal transition (EMT) genes, including Slug and Snail, and promoted cell migration by recruiting HMGA2 in the human EOC cell line A2780. Bach1 overexpression enhanced and Bach1 knockout reduced the expression of Slug and the metastasis of EOC 137234-62-9 in a tumor metastasis mouse model. Bach1 expression was positively correlated with Slug and HMGA2 expression in human ovarian cancer tissues. In addition, Bach1 activated p-AKT and p-p70S6K, increased the expression of cyclin D1, and promoted the growth of ovarian cancer cells in vitro and tumor xenografts in vivo. Together, our findings reveal that Bach1 enhances tumor growth and recruits HMGA2 to promote EMT and ovarian cancer metastasis.
Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy. Due to the lack of eﬀective screening methods for ovarian cancer, 75% of patients are diagnosed with advanced disease . To date, the main treatment for ovarian cancer is surgery followed by combination chemotherapy. While the majority of patients respond to treatment, most patients will die from distant metastasis and relapse such that the survival rate for patients with advanced-stage disease remains low . Therefore, a better understanding of the mechanisms of EOC metastasis may help provide a therapeutic strategy for meta-static ovarian cancer.
BTB and CNC homology 1 (Bach1) is a ubiquitously expressed transcriptional factor and a member of the Cap ‘n’ Collar and basic region leucine zipper factor (CNC-bZip) family. Bach1 acts as a tran-scriptional repressor by heterodimerizing with small Maf proteins and inhibiting the transcription of various genes dependent on Maf-re-cognition elements (MAREs), such as heme oxygenase-1 (HO-1). Bach1
plays a key role in the regulation of oxidative stress, heme oxidation, the cell cycle, hematopoiesis, and immunity [3–5]. We have shown that Bach1 impairs both developmental angiogenesis in zebrafish embryos and the angiogenic response to peripheral ischemic injury in adult mice [6,7]. In contrast with its role as a transcriptional repressor, Bach1 also acts as an activator of metastatic genes such as CXCR4 and MMP1, and it has been associated with bone metastasis in breast cancer [8,9]. The expression of Bach1 and its target genes has been linked to a higher risk of breast cancer recurrence in patients  as well as increases in cancer cell invasion and migration in human colorectal cancer and prostate cancer [10–12], whereas lower Bach1 levels have been associated with decreases in breast cancer metastasis . However, the detailed role of Bach1 in the regulation of EOC metastasis and growth remains un-clear.
Epithelial-mesenchymal transition (EMT) is an important process during embryonic cell layer movement and tissue repair. EMT con-tributes to cancer progression and metastasis and might also help chemoresistant cancer cells acquire enhanced motility . During
∗∗∗ Corresponding author. 130 Dongan Road, Shanghai, 200032, China. E-mail addresses: [email protected] (X. Zhi), [email protected] (L. Yao), [email protected] (D. Meng). 1 Wenyan Han, Yiqun Zhang and Cong Niu contributed equally to this work.
EMT, adherent epithelial cells are converted to motile mesenchymal cells characterized by increased expression of mesenchymal markers (vimentin, thrombospondin, N-cadherin, and vitronectin) and de-creased expression of epithelial markers (E-cadherin, collagen IV, oc-cludin, and desmoplakin) . Several transcriptional repressors, such as the zinc finger factors Snail and Slug and the basic helix-loop-helix (bHLH) transcription factor Twist, have been implicated in the onset of EMT in mammary epithelial cells . High-mobility group AT-hook protein 2 (HMGA2) is a critical factor for TGF-β-induced EMT in mouse mammary epithelial cells; it directly binds to the Snail promoter and acts as a transcriptional regulator of Snail expression . HMGA2 has been shown to promote metastasis and drug resistance in cancers , and increased HMGA2 expression is associated with EMT in ovarian cancer . r>