CBX7 regulates stem cell-like properties of gastric cancer cells via p16 and AKT-NF-κB-miR-21 pathways

Abstract

BackgroundChromobox protein homolog 7 (CBX7), a member of the polycomb group (PcG) family of proteins, is involved in the regulation of cell proliferation and cancer progression. PcG family members, such as BMI, Mel-18, and EZH2, are integral constituents of the polycomb repressive complexes (PRCs) and have been known to regulate cancer stem cell (CSC) phenotype. However, the role of other PRCs’ constituents such as CBX7 in the regulation of CSC phenotype remains largely elusive. This study was to investigate the role of CBX7 in regulating stem cell-like properties of gastric cancer and the underlying mechanisms.MethodsFirstly, the role of CBX7 in regulating stem cell-like properties of gastric cancer was investigated using sphere formation, Western blot, and xenograft tumor assays. Next, RNA interference and ectopic CBX7 expression were employed to determine the impact of CBX7 on the expression of CSC marker proteins and CSC characteristics. The expression of CBX7, its downstream targets, and stem cell markers were analyzed in gastric stem cell spheres, common cancer cells, and gastric cancer tissues. Finally, the pathways by which CBX7 regulates stem cell-like properties of gastric cancer were explored.ResultsWe found that CBX7, a constituent of the polycomb repressive complex 1 (PRC1), plays an important role in maintaining stem cell-like characteristics of gastric cancer cells via the activation of AKT pathway and the downregulation of p16. Spearman rank correlation analysis showed positive correlations among the expression of CBX7 and phospho-AKT (pAKT), stem cell markers OCT-4, and CD133 in gastric cancer tissues. In addition, CBX7 was found to upregulate microRNA-21 (miR-21) via the activation of AKT-NF-κB pathway, and miR-21 contributes to CBX7-mediated CSC characteristics.ConclusionsCBX7 positively regulates stem cell-like characteristics of gastric cancer cells by inhibiting p16 and activating AKT-NF-κB-miR-21 pathway.Electronic supplementary materialThe online version of this article (10.1186/s13045-018-0562-z) contains supplementary material, which is available to authorized users.

Celastrol inhibits growth and metastasis of human gastric cancer cell MKN45 by down‐regulating microRNA‐21

“…In addition, previous studies demonstrated that celastrol inhibited the PI3K/AKT and NF-κB survival pathway in human breast cancer (Shrivastava, Jeengar, Reddy, Reddy, & Naidu, 2015). Moreover, miR-21 can affect cancer cell growth via regulating the PTEN/AKT and NF-κB pathways (He et al, 2015;Ni et al, 2018;S. M. Yang et al, 2013).…”

“…In addition, previous studies demonstrated that celastrol inhibited the PI3K/AKT and NF‐κB survival pathway in human breast cancer (Shrivastava, Jeengar, Reddy, Reddy, & Naidu, ). Moreover, miR‐21 can affect cancer cell growth via regulating the PTEN/AKT and NF‐κB pathways (He et al, ; Ni et al, ; S. M. Yang et al, ). Furthermore, PTEN/PI3K/AKT and NF‐κB signaling pathways are often involved in gastric cancer (Baud & Karin, ; Colombo, Zambrano, & Agresti, ; He et al, ; Sha et al, ).…”

MicroRNAs and the PTEN/PI3K/Akt pathway in gastric cancer (Review)

“…In addition, miR-21 was involved in the regulation of a number of Polycomb group (PcG) proteins on gastric cancer stem cells (CSCs), a small subset of cancer cells with self-renewal and tumor-initiating properties, which are critical in tumor metastasis, recurrence and chemoresistance (70). PcG family proteins, including polycomb group RING finger protein 2 (Mel-18), chromobox homolog 7 (CBX7) and enhancer of zeste homolog 2, form the multi-protein complexes, called polycomb repressive complexes, through which they epigenetically regulate homeotic genes expression by altering chromosomal structure or transcriptional repression (71). In this manner, PcG proteins exert effects in embryonic development, cell proliferation and differentiation, stem cell properties and tumorigenesis (71).…”

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

“…MiR‐29b promotes cisplatin resistance in GC cells via the PI3K/Akt signaling pathway . Apart from serving roles downstream of the PI3K/Akt pathway, NF‐κB used to be moreover capable to have an effect on the expression of PTEN and downstream Akt signaling, mediated through its transcriptional regulation of miRNAs, consisting of miR‐425 and miR‐21 . Moreover, the tumor suppressor miR‐218 regulates COX‐2 through the antiapoptotic NF‐κB signaling pathway .…”

“…122 Apart from serving roles downstream of the PI3K/Akt pathway, NF-κB used to be moreover capable to have an effect on the expression of PTEN and downstream Akt signaling, mediated through its transcriptional regulation of miRNAs, consisting of miR-425 and miR-21. 123,124 Moreover, the tumor suppressor miR-218 regulates COX-2 through the antiapoptotic NF-κB signaling pathway. 125 OncomiR-370 used to be shown to decrease TGFβ -RII expression and stimulate TGFβ-1-induced phosphorylation of Smad3.…”