A Regulatory Loop Involving miR-22, Sp1, and c-Myc Modulates CD147 Expression in Breast Cancer Invasion and Metastasis

Abstract

Breast cancer is the most common cancer in women for which the metastatic process is still poorly understood. CD147 is upregulated in breast cancer and has been associated with tumor progression, but little is known about its regulatory mechanisms. In this study, we demonstrated that CD147 was overexpressed in breast cancer tissues and cell lines, and the high expression correlated with tumor invasion and metastasis. We also found that the transcription factors Sp1 and c-Myc could bind to the CD147 promoter and enhance its expression. The CD147 mRNA has a 748-bp 3 0 -untranslated region (UTR) with many miRNA target sites, suggesting possible regulation by miRNAs. We discovered that miR-22 repressed CD147 expression by directly targeting the CD147 3 0 UTR. We also determined that miR-22 could indirectly participate in CD147 modulation by downregulating Sp1 expression. miR-22 could form an autoregulatory loop with Sp1, which repressed miR-22 transcription by binding to the miR-22 promoter. Together with the c-Myc-mediated inhibition of miR-22 expression, our investigation identified a miR-22/Sp1/c-Myc network that regulates CD147 gene transcription. In addition, miR-22 overexpression suppressed breast cancer cell invasion, metastasis, and proliferation by targeting CD147 in vitro and in vivo. Furthermore, we found that miR-22 was significantly downregulated in breast cancer tissues and that its expression was inversely correlated with the tumor-node-metastasis stage and lymphatic metastasis in patients. Our study provides the first evidence that an miR-22/Sp1/c-Myc network regulates CD147 upregulation in breast cancer and that miR-22 represses breast cancer invasive and metastatic capacities. Cancer Res; 74(14); 3764-78. Ó2014 AACR.

Overexpression of REIC/Dkk-3 suppresses the expression of CD147 and inhibits the proliferation of human bladder cancer cells

“…With regard to the regulation of CD147 expression, several signaling pathways are reported to be associated with its transcription (18)(19)(20)(21)(22)(23). The core promoter and transcription factor-binding sites of CD147 were previously analyzed and identified as targets of the cancer-associated transcription factors c-Myc and Sp1 (22,23).…”

“…The core promoter and transcription factor-binding sites of CD147 were previously analyzed and identified as targets of the cancer-associated transcription factors c-Myc and Sp1 (22,23). Since the expression of CD147 is known to be positively regulated by p38-, Erk1/2-and JNK-dependent MAPK signaling and c-Myc protein, the associations between CD147 expression, MAPK pathway activation and the expression of c-Myc following Ad-REIC treatment were examined in the present study.…”

“…With regard to the regulation of the expression of CD147, several signaling pathways are reported to be associated with its gene transcription (18)(19)(20)(21)(22)(23). In particular, the expression of CD147 is reported to be positively regulated by p38-, Erk1/2-and JNK-dependent MAPK signaling pathways and the c-Myc protein (18,19,21,22).…”

“…In particular, the expression of CD147 is reported to be positively regulated by p38-, Erk1/2-and JNK-dependent MAPK signaling pathways and the c-Myc protein (18,19,21,22). The associations between CD147 expression, phosphorylation of MAPK pathway components, and the expression of c-Myc following Ad-REIC treatment was examined.…”

Noncoding RNAs in breast cancer

“…Some of the miRNAs downregulated in DCIS are implicated in the downregulation of anti-apoptotic factors, including BCL2 (miR-143, miR195) [88,99,123], Survivin (miR-143) [89], Bcl-w (miR-497) [105] and 14-3-3f (miR-451) [103] (Table 1). In addition, these identified tumor-suppressive miRNAs also functionally target other biological processes including cell-cycle progression (Cyclin D1, targeted by miR-143) [89], angiogenesis (vascular endothelial growth factor A [VEGFA], targeted by miR-145 and miR-185) [91,96], epigenetic regulation (TET1-3, targeted by miR-22; DNA (cytosine-5)-methyltransferase 1 [DNMT1], targeted by miR-185) [79,95], Rho-dependent signal transduction (RTKN, targeted by miR-145) [92], invasion (ADP ribosylation factor 6 [ARF6], targeted by miR-145; CD147, targeted by miR-22; Six1, targeted by miR-204; Smad3, targeted by miR-489) [80,93,100,104] and degradation of the extracellular matrix (ECM) (urokinase plasminogen activator, uPA, targeted by miR-193 b) [97] (Table 1).…”