Abstract
BackgroundA-Kinase interacting protein 1 (AKIP1) relates to gastric cancer growth, metastasis, and prognosis, while its regulation on gastric cancer invasion and stemness under hypoxia microenvironment is not reported. Therefore, this study aimed to explore this topic to uncover AKIP1’s role in gastric cancer under hypoxia.MethodsGastric cancer cell lines AGS and MKN45 were cultured under hypoxia condition, then transfected with AKIP1 or negative control (NC) overexpression plasmid or AKIP1 or NC knockdown plasmid. Furthermore, rescue experiments were conducted by transfecting HIF-1α or β-catenin overexpression plasmid, combined with AKIP1 or NC knockdown plasmid. Afterward, cell invasion, CD133+ cell proportion, sphere number/1,000 cells, and HIF-1α and β-catenin pathways were measured.ResultsThe invasive cell count, CD133+ cell proportion, and sphere number/1,000 cells were enhanced in both AGS cells and MKN45 cells under hypoxia, and AKIP1 expression was also elevated. AKIP1 knockdown inhibited cell invasion, CD133+ cell proportion, sphere number/1,000 cells, HIF-1α, vascular endothelial growth factor (VEGF), β-catenin, and calcium-binding protein (CBP) expressions in AGS cells and MKN45 cells under hypoxia, while AKIP1 overexpression presented with the opposite effect. Then, in rescue experiments, HIF-1α overexpression and β-catenin overexpression both promoted cell invasion, CD133+ cell proportion, and sphere number/1,000 cells, which also attenuated the effect of AKIP1 knockdown on these functions in AGS cells and MKN45 cells.ConclusionAKIP1 promotes cell invasion and stemness via activating HIF-1α and β-catenin signaling pathways in gastric cancer under hypoxia condition.
Highlights
Gastric cancer remains to be one of the most frequent and fatal cancers in the world, despite the reduction in risk factors such as Helicobacter pylori [1–4]
Similar trends were observed in MKN45 cells. These suggested that A-Kinase interacting protein 1 (AKIP1) might be engaged in the hypoxia-induced cell invasion and stemness in gastric cancer
In AGS cells, the invasive cell count was elevated in the hypoxia-inducible factor 1 subunit alpha (HIF-1a)(+) group compared with thar in the negative control (NC) group (p < 0.01); besides, the invasive cell count was elevated in the HIF-1a(+)&AKIP1(−) group compared with that in the AKIP1(−) group (p < 0.01), but it was still declined in the HIF-1a(+)&AKIP1(−) group compared with that in the HIF1a(+) group (p < 0.01). These findings indicated that HIF-1a overexpression elevated invasive cell count, and HIF-1a overexpression might diminish the effect of AKIP1 knockdown on invasive cell count to some extent; in addition, the invasive cell count was elevated in the b-catenin(+) group compared with that in the NC group (p < 0.01), besides the invasive cell count was elevated in the b-catenin(+)&AKIP1(−) group compared with that in the AKIP1(−) group (p < 0.01), but it was still declined in the b-catenin(+)&AKIP1(−) group compared with that in the b-catenin(+) group (p < 0.01)
Summary
Gastric cancer remains to be one of the most frequent and fatal cancers in the world, despite the reduction in risk factors such as Helicobacter pylori [1–4]. AKIP1 is a promising oncology-related factor in recent studies. AKIP1 is upregulated in several cancers, and it correlates with more deteriorative tumor features and survival profiles in these cancer patients, which suggests that it participates in the progression of many cancers [15–19]. There is correlation between AKIP1 and gastric cancer, which elucidates that it is involved in tumor progression through the modulation of Slug-induced epithelial–mesenchymal transition, which enhances growth and metastasis of the tumor [20]. AKIP1 may be involved in the regulation of gastric cancer pathogenesis under hypoxia, while there is no evidence supporting this presumption. A-Kinase interacting protein 1 (AKIP1) relates to gastric cancer growth, metastasis, and prognosis, while its regulation on gastric cancer invasion and stemness under hypoxia microenvironment is not reported. This study aimed to explore this topic to uncover AKIP1’s role in gastric cancer under hypoxia
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