J Cancer 2022; 13(8):2644-2655. doi:10.7150/jca.69970 This issue

Research Paper

The Curcumin Analog Da0324 Inhibits the Proliferation of Gastric Cancer Cells via HOTAIRM1/miR-29b-1-5p/PHLPP1 Axis

Fanfan Xu1*, Mengxia Chen1*, Hao Chen1, Nan Wu1, Qinqin Qi3, Xiujiao Jiang3, Daoquan Fang3, Qian Feng1, Rong Jin1,2✉, Lei Jiang3✉

1. Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
2. Department of Epidemiology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
3. Central Laboratory, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
*These authors contributed equally to this paper.

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Citation:
Xu F, Chen M, Chen H, Wu N, Qi Q, Jiang X, Fang D, Feng Q, Jin R, Jiang L. The Curcumin Analog Da0324 Inhibits the Proliferation of Gastric Cancer Cells via HOTAIRM1/miR-29b-1-5p/PHLPP1 Axis. J Cancer 2022; 13(8):2644-2655. doi:10.7150/jca.69970. Available from https://www.jcancer.org/v13p2644.htm

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Abstract

Graphic abstract

Background: Our previous study has shown that Da0324, a curcumin analog, exhibited significantly improved stability and antitumor activity. However, the molecular mechanisms of action of Da0324 remain poorly understood. Long non-coding RNA (lncRNA) has been shown to play a key role in tumor progression. Here, we aim to investigate the molecular mechanisms underlying the anti-cancer activity of Da0324 by regulating the lncRNA HOTAIRM1.

Methods: Gastric cancer cell lines were treated with Da0324 and/or transfected with lentiviral vector expressing HOTAIRM1 shRNA, and/or miR-29b-1-5p mimics and/or small interference RNA (siRNA) against PHLPP1, or HOTAIRM1 siRNA or lentiviral vector expressing HOTAIRM1, as needed. The expression of HOTAIRM1, miR-29b-1-5p and PHLPP1 in GC cells was determined by Real-Time PCR. Cell growth was examined by CCK-8 assay and colony formation assay in vitro. The targeted relationship between HOTAIRM1 and miR-29b-1-5p was verified by luciferase reporter gene assay. PHLPP1 protein expression was examined by Western blotting.

Results: Da0324 increased the expression of HOTAIRM1 in GC cells. HOTAIRM1 expression was significantly down-regulated in GC tissues, and the low expression of HOTAIRM1 was associated with the shorter survival rate of GC patients based on the TCGA database. Knockdown of HOTAIRM1 promoted GC cell proliferation whereas overexpression of HOTAIRM1 inhibited GC cell proliferation as demonstrated by CCK-8 and colony formation assays. Moreover, knockdown of HOTAIRM1 reversed the Da0324-mediated growth inhibition of GC cells. Furthermore, HOTAIRM1 acted as a sponge for miR-29b-1-5p and PHLPP1 is regulated by the HOTAIRM1/miR-29b-1-5p axis in GC cells. Overexpression of miR-29b-1-5p or knockdown of PHLPP1 reversed the ability of Da0324 to inhibit the growth of GC cells.

Conclusions: Our data suggest that Da0324 exerts antitumor activity by regulating HOTAIRM1/miR-29b-1-5p/PHLPP1 axis in GC cells, and provide new insights into the anti-cancer mechanism of Da0324.

Keywords: curcumin analog, Da0324, gastric cancer, HOTAIRM1, miR-29b-1-5p, PHLPP1