Silencing of hypoxia‑inducible adrenomedullin using RNA interference attenuates hepatocellular carcinoma cell growth in vivo.

Adrenomedullin (ADM) is an angiogenic peptide that has been shown to increase the risk of endometrial hyperplasia and to promote tumor cell survival following hypoxia. ADM may induce microvessel proliferation and partially decrease hypoxia in solid tumors, thus contributing to the proliferation of tumor cells, as well as tumor invasion and metastasis. However, the impact of hypoxia‑induced ADM expression on hepatocellular carcinoma (HCC) cells requires further elucidation. In the present study it was found that the levels of ADM mRNA in tumor tissue from patients with HCC were significantly increased compared with the mRNA levels in adjacent non‑tumorous liver tissue. Under hypoxic conditions, the mRNA and protein levels of ADM, as well as those of the cancer‑promoting genes vascular endothelial growth factor and hypoxia‑inducible factor 1α, were significantly elevated in a time‑dependent manner in three human HCC cell lines. In addition, knockdown of ADM expression using short hairpin RNA (shRNA) in SMMC‑7721 cells resulted in apoptosis that was not observed in untransfected cells. Furthermore, combined treatment with cisplatin and ADM‑shRNA significantly decreased tumor growth in vivo compared with treatment with cisplatin or ADM‑shRNA alone. These data demonstrate that ADM acts as a critical promoter of cell cycle progression in HCC and that the inhibition of ADM may be an effective interventional therapeutic strategy in HCC.