A-Kinase Interacting Protein 1 Promotes Cell Invasion and Stemness via Activating HIF-1α and β-Catenin Signaling Pathways in Gastric Cancer Under Hypoxia Condition

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.

Hypoxia differently regulates the proportion of ALDHhi cells in lung squamous carcinoma H520 and adenocarcinoma A549 cells via the Wnt/β‐catenin pathway

“…Previous studies have established the association between the Wnt/β‐catenin pathway and hypoxia. Researchers found that the activation of hypoxia‐inducible factor 1α (HIF‐1α) and β‐catenin promoted cell invasion and stemness in gastric cancer cell lines under hypoxic conditions 34 . Moreover, hypoxia‐activated Wnt signaling in induced pluripotent stem cells (iPS cells) and then impaired their differentiation into cardiomyocyte 35 .…”

“…Researchers found that the activation of hypoxia‐inducible factor 1α (HIF‐1α) and β‐catenin promoted cell invasion and stemness in gastric cancer cell lines under hypoxic conditions. 34 Moreover, hypoxia‐activated Wnt signaling in induced pluripotent stem cells (iPS cells) and then impaired their differentiation into cardiomyocyte. 35 Conversely, hypoxia suppressed Wnt/β‐catenin pathway by upregulating the expression of HIF proteins in human osteosarcoma cell.…”

HIF in Gastric Cancer: Regulation and Therapeutic Target

“…Zhenqin Luo et al found that HIF1α can promote the progression of gastric cancer by promoting the stemness of gastric cancer cells [ 92 ] ( Table 6 ). On the other hand, Zhi-Feng Miao et al proved that HIF1α promotes peritoneal dissemination by promoting the stemness of gastric cancer cells [ 93 ].…”

Brusatol inhibits the growth of prostate cancer cells and reduces HIF-1α/VEGF expression and glycolysis under hypoxia

“…As a transcription factor, HIF-1α promotes the transcription of VEGF and then cooperatively stimulates various cancer cells to acquire invasion and metastasis as well as drives tumor progression (Lu et al, 2002;Semenza, 2003). For instance, activated HIF-1α and VEGF play a part in facilitating metastasis and angiogenesis, relevant to the poor prognosis of gastric cancer (Luo et al, 2021;Mu et al, 2021). Therapeutically targeting HIF-1α reduces and inhibits growth and metastasis of relapsed anaplastic Wilms tumor .…”