Hydrostatic pressure stabilizes HIF-1α expression in cancer cells to protect against oxidative damage during metastasis

Abstract

The tissue microenvironment is known to play a pivotal role in cancer metastasis. Interstitial fluid hydrostatic pressure generally increases along with the rapid growth of malignant tumors. The aim of the present study was to investigate the role and relevant mechanism of elevated hydrostatic pressure in promoting the metastasis of cancer cells. Using a commercial device, Lewis lung cancer (LLC) cells were exposed to 50 mmHg hydrostatic pressure (HP) for 24 h. The survival time and morphology of the cells did not notably change; however, the results from a PCR array revealed the upregulation of numerous metastasis-promoting genes (Hgf, Cdh11 and Ephb2) and the downregulation of metastasis suppressing genes (Kiss1, Syk and Htatip2). In addition, compared with that in the control, the cells which had undergone exposure to 50 mmHg HP showed significantly higher protein expression level of HIF-1α and the antioxidant enzymes, SOD1 and SOD2, as well as improved tolerance to oxidative stress (P<0.05 vs. control). Following an intravenous injection of the LLC cells into healthy mice, to induce lung metastasis, it was found that the exposure of the LLC cells to 50 mmHg HP for 24 h, prior to injection into the mice, resulted in higher cell survival/retention in the lungs 24 h later and also resulted in more metastatic tumor lesions 4 weeks later (P<0.05 vs. control). Further investigation is required to confirm the molecular mechanism; however, the results from the present study suggested that elevated interstitial fluid HP in malignant tumors may promote the metastasis of cancer cells by stabilizing HIF-1α expression to defend against oxidative damage.