Decoding hepatocellular carcinoma: the promise of microRNAs

Hepatocellular carcinoma (HCC) is the most common primary liver cancer with rising incidence and mortality worldwide. While advances in surgical, transplantation, and regional therapies have made an impact in treatment, the highly vascular nature of the tumor and tendency to metastasize make systemic treatment necessary for the majority of patients. In the past five years, molecularly targeted therapies have been developed with modest success. Most notably, sorafenib (Nexavar), an oral multi-kinase inhibitor of the vascular endothelial growth factor receptor (VEGFR) demonstrated improved survival (1). Unfortunately, the benefit of sorafenib is short-lived, and despite numerous clinical trials, no other VEGF-targeting agent has clearly shown efficacy in randomized studies (2-4). Therefore, it is essential to understand drivers of HCC other than the classic VEGF pathway.

MicroRNAs (miRNAs) have been implicated in multiple biological pathways and dysregulation of miRNAs has been shown in many human tumors, including HCC (5). Specifically miR-26a has previously been shown to be downregulated in metastatic HCC patient samples when compared to non-metastatic samples, indicating that the target of miR-26a may be involved in tumor migration and invasion (6). The target mRNA, however was unknown. In the study by Yang et al. (7), the authors identified hepatocyte growth factor (HGF) as the target of miR-26a and showed that expression of miR-26a can result in in vitro inhibition of proliferation and migration as well as in vivo inhibition of angiogenesis in mice. They demonstrate that miR-26a acts as a tumor suppressor by targeting HGF and subsequent down-regulation of the HGF-MET signaling proteins and VEGFA. Increased expression of miR-26a correlated with decreased expression of VEGFA and decreased microvessel density, indicating that miR-26a functions to inhibit angiogenesis. Moreover, the authors show that the expression of miR-26a is an independent prognostic marker for overall survival and time to recurrence in HCC patients. Patients with high HGF levels, low miR-26a levels, high VEGFA, and high microvessel density had worse overall survival and a higher likelihood of tumor recurrence compared to patients with low HGF levels.

Tissue biomarkers are sorely lacking for HCC. The ability to make the diagnosis of HCC without a biopsy has hindered the ability to develop prognostic and predictive markers for our patients. Levels of miR-26a may serve as a prognostic marker and should be explored as a possible predictor for response to inhibition of angiogenesis. In order to confirm these data and identify new biomarkers, tissue studies must be incorporated into clinical trials of HCC. Recently, the association of benefit in patients with MET-high tumors treated with tivantinib, an inhibitor of the MET pathway, demonstrates that a biopsy can be quite revealing in HCC (8).

Even more intriguing than its role as a biomarker, miR-26a could be a new opportunity for treatment of HCC. Ultimately, if miRNAs can be delivered successfully in the clinic, mimics of miR-26a should lead to inhibition of proliferation, migration and angiogenesis. The mechanism would be postulated to be complementary to both MET and VEGF inhibition. A cancer-targeting miRNA mimic of another miRNA, miR-34 (MRX34), is in phase I clinical trials in HCC and recruiting patients (NCT01829971). MicroRNA therapy is an unproven frontier in drug development, but we have learned from experience that successful HCC treatment will require a radical new approach.

Acknowledgements

Disclosure: The authors declare no conflict of interest.

References

1. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378-90. [PubMed]
2. Johnson PJ, Qin S, Park JW, et al. Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL study. J Clin Oncol 2013;31:3517-24. [PubMed]
3. Llovet JM, Decaens T, Raoul JL, et al. Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: results from the randomized phase III BRISK-PS study. J Clin Oncol 2013;31:3509-16. [PubMed]
4. Cheng AL, Kang YK, Lin DY, et al. Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial. J Clin Oncol 2013;31:4067-75. [PubMed]
5. Budhu A, Jia HL, Forgues M, et al. Identification of metastasis-related microRNAs in hepatocellular carcinoma. Hepatology 2008;47:897-907. [PubMed]
6. Yang X, Liang L, Zhang XF, et al. MicroRNA-26a suppresses tumor growth and metastasis of human hepatocellular carcinoma by targeting interleukin-6-Stat3 pathway. Hepatology 2013;58:158-70. [PubMed]
7. Yang X, Zhang XF, Lu X, et al. MicroRNA-26a suppresses angiogenesis in human hepatocellular carcinoma by targeting HGF-cmet pathway. Hepatology 2013. [Epub ahead of print].
8. Santoro A, Rimassa L, Borbath I, et al. Tivantinib for second-line treatment of advanced hepatocellular carcinoma: a randomised, placebo-controlled phase 2 study. Lancet Oncol 2013;14:55-63. [PubMed]