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

Abstract

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.

Targeting Adrenomedullin in Oncology: A Feasible Strategy With Potential as Much More Than an Alternative Anti-Angiogenic Therapy

“…Furthermore, It was observed that AM could be an upstream modulator of the HIF-1a/VEGF pathway, suggesting that AM might induce angiogenesis through VEGF expression as consequence of JNK and AP-1 activation in epithelial ovarian cancer (6,7). Analogously, several in vitro and in vivo studies have demonstrated the involvement of hypoxia, HIF-1a, AM, and AM receptors in HCC development, and how anti-AM therapeutic approaches would be of great value to deal with this disease (164)(165)(166).…”

Identification of a novel Gene Signature and potential mechanisms related to Targeted Drug Resistance in Hepatocellular Carcinoma Based on integrating bioinformatics and machine learning

“…Adrenomedullin (ADM) has the ability to induce microvascular proliferation of solid tumors and promote tumor proliferation and migration (33). Knockdown of ADM can increase the sensitivity of cisplatin to hepatoma cells (34). TNF alpha induced protein 3 (TNFAIP3) can induce EMT and promote metastasis in most tumors (35,36).…”

Peptidergic Systems and Cancer: Focus on Tachykinin and Calcitonin/Calcitonin Gene-Related Peptide Families

“…Hepatocellular carcinoma cells express AM and its receptor and, under hypoxic conditions, favor AM expression [ 226 ]; in addition, AM mRNA, HIF-1α and VEGF levels were increased under the same conditions in human hepatocellular carcinoma cell lines [ 229 ]. CLR, RAMP2, and RAMP3 have been reported in liver cancer, and a high AM level has been related to increased intrahepatic metastasis [ 226 , 227 ].…”

“…AM, through Akt activation, promoted the growth of hepatocellular carcinoma cells, which was inhibited with AM inhibitors [ 226 ]. Knockdown of AM expression promoted apoptotic mechanisms in hepatocellular carcinoma cells and, combined with cisplatin, significantly decreased tumor growth when compared with knockdown of AM expression or cisplatin alone [ 229 ]. The data show the association of AM with hepatocellular carcinoma development.…”

“…Consequently, AM level could be a prognostic factor in hepatocellular carcinoma. Additionally, in patients with this disease, AM mRNA levels were higher in tumor tissues than in adjacent nontumor liver tissues [ 229 ].…”