Upregulated miR‐132 in Lgr5⁺ gastric cancer stem cell‐like cells contributes to cisplatin‐resistance via SIRT1/CREB/ABCG2 signaling pathway

Abstract

Cisplatin resistance has long been a major problem that restricts its use. A novel paradigm in tumor biology suggests that gastric tumor chemo-resistance is driven by gastric cancer stem cell-like (GCSCs). Growing evidence has indicated that microRNAs (miRNAs) contributes to chemo-resistance in gastric cancer (GC). Here, Lgr5 cells derived from gastric cancer cell lines displayed stem cell-like features. Flow cytometry demonstrated the presence of a variable fraction of Lgr5 in 19 out of 20 GC specimens. By comparing the miRNA expression profiles of Lgr5 GCSCs and Lrg5 cells, we established the upregulation of miR-132 in Lgr5 GCSCs. The enhanced miR-132 expression correlated chemo-resistance in GC patients. Kaplan-Meier survival curve showed that patients with low miR-132 expression survived obviously longer. Functional assays results indicated that miR-132 promoted cisplatin resistance in Lgr5 GCSCs in vitro and in vivo. Further dual-luciferase reporter gene assays revealed that SIRT1 was the direct target of miR-132. The expression of miR-132 was inversely correlated with SIRT1 in gastric cancer specimens. Furthermore, through PCR array we discovered ABCG2 was one of the downstream targets of SIRT1. Overexpression of SIRT1 down-regulated ABCG2 expression by promoting the de-acetylation of the transcription factor CREB. CREB was further activated ABCG2 via binding to the promoter of ABCG2 to induce transcription. Thus, we concluded that miR-132 regulated SIRT1/CREB/ABCG2 signaling pathway contributing to the cisplatin resistance and might serve as a novel therapeutic target against gastric cancer.

Gastric cancer: Basic aspects

“…recently described an upregulation of miR‐501‐5p in GC cell lines and specimens from patients with GC, functioning as an activator of the Wnt/β‐catenin signaling pathway and enhancing the CSC‐phenotype. MiR‐132 has been also found to be upregulated in Lgr5 + GCSC‐like cells in GC specimens, in correlation with chemoresistance and worse survival . In vitro, miR‐132 promoted resistance to cisplatin through the inhibition of SIRT, which results in enhanced expression of the transporter ABCG2, previously identified in multidrug resistance .…”

How to overcome ATP-binding cassette drug efflux transporter-mediated drug resistance?

“…For example, it was seen that miR-132 enhanced cisplatin resistance in gastric cancer cells by targeting SIRT1 which regulates ABCG2 expression by promoting the de-acetylation of the transcription factor CREB (SIRT1/CREB/ABCG2 pathway). Moreover, Kaplan-Meier survival analysis showed that low miR-132 is related to longer survival in chemo resistant gastric cancer [206] . Another example is Wnt/β-catenin-ABCG2 pathway, which is modulated by miR-199a/b in colorectal cancer stem cells, and whose upregulation is related to cisplatin resistance [207] .…”

“…Use of microRNA has revealed a more complex role of ABCG2 in drug resistance related signaling pathways: SIRT1/CREB/ABCG2 and Wnt/β-catenin-ABCG2 pathway Breast, ovarian cancer, other cell lines [200][201][202][203][204][205][206][207] TKI: tyrosine kinase inhibitor; MDR: multidrug resistance; CML: chronic myeloid leukemia; NSCLC: non-small cell lung cancer their inhibition will also increase the oral bioavailability of the drug, in addition to its penetration to the tumor site. However, since these two transporters are also expressed in sanctuary sites, caution for potential toxic side effects should be considered.…”

Dysregulation of miRNAs as a signature for diagnosis and prognosis of gastric cancer and their involvement in the mechanism underlying gastric carcinogenesis and progression

“…The miR‐145 targeting of CD44 plays fundamental roles in the modulation of cancer growth and MDR in GC, and the miR‐129 targeting of P‐gp regulates DDP resistance in GC cells . Other miRNAs, such as miR‐132, miR‐524‐5p, miR‐34a, and miR‐200c (200–202) also promote resistance to DDP in GC. In a current study, miRNA‐132 was verified to promote cisplatin resistance in a GC stem cell‐like Lgr5 cells both in vitro and in vivo, which used to be mediated through the regulation of SIRT1/CREB/ABCG2 signaling pathway .…”

“…Other miRNAs, such as miR‐132, miR‐524‐5p, miR‐34a, and miR‐200c (200–202) also promote resistance to DDP in GC. In a current study, miRNA‐132 was verified to promote cisplatin resistance in a GC stem cell‐like Lgr5 cells both in vitro and in vivo, which used to be mediated through the regulation of SIRT1/CREB/ABCG2 signaling pathway . The sensitivity of GC cells to cisplatin can enhance by a low expression level of miR‐99a and miR‐491 through targeting CAPNS1/calpain1/calpain2/caspase‐3/PARP1 signaling pathway directly …”