MicroRNAs involved in tumor suppressor and oncogene pathways: implications for hepatobiliary neoplasia

Abstract

MicroRNAs are a class of small regulatory RNAs that function to modulate protein expression. This control allows for fine-tuning of the cellular phenotype, including regulation of proliferation, cell signaling, and apoptosis; not surprisingly, microRNAs contribute to liver cancer biology. Recent investigations in human liver cancers and tumor-derived cell lines have demonstrated decreased or increased expression of particular microRNAs in hepatobiliary cancer cells. Based on predicted and validated protein targets as well as functional consequences of altered expression, microRNAs with decreased expression in liver tumor cells may normally aid in limiting neoplastic transformation. Conversely, selected microRNAs that are up-regulated in liver tumor cells can promote malignant features, contributing to carcinogenesis. In addition, microRNAs themselves are subject to regulated expression, including regulation by tumor suppressor and oncogene pathways. This review will focus on the expression and function of cancer-related microRNAs, including their intimate involvement in tumor suppressor and oncogene signaling networks relevant to hepatobiliary neoplasia.

Figure 1. MicroRNA Expression and Processing

(A) MicroRNAs are expressed as primary transcripts and processed by the microprocessor in the nucleus to precursor microRNAs. For the TGF-β responsive mir-21 and mir-199a, interaction of SMAD proteins with the p68 helicase in the microprocessor increases processing to the precursor, facilitating expression via processing. The precursor is exported for subsequent cleavage by Dicer in the cytoplasm. The mature microRNA is loaded into the RISC complex and suppresses translation of target mRNAs. (B) The mature microRNA is 19–23 nucleotides in length, with the specificity-determining seed region (nucleotides 2–7) at the 5’ end. MicroRNA family members generally share an identical seed and differ at only a few positions overall (underlined). The mir-17–92 cluster is illustrated, demonstrating the seed (bold) as well as the high degree of similarity of family members (mir-17 and mir-20a). Note that the mir-18 sequence is similar to mir-17 and mir-20a but has a different seed sequence, indicating a different set of targets.

Figure 1. MicroRNA Expression and Processing

(A) MicroRNAs are expressed as primary transcripts and processed by the microprocessor in the nucleus to precursor microRNAs. For the TGF-β responsive mir-21 and mir-199a, interaction of SMAD proteins with the p68 helicase in the microprocessor increases processing to the precursor, facilitating expression via processing. The precursor is exported for subsequent cleavage by Dicer in the cytoplasm. The mature microRNA is loaded into the RISC complex and suppresses translation of target mRNAs. (B) The mature microRNA is 19–23 nucleotides in length, with the specificity-determining seed region (nucleotides 2–7) at the 5’ end. MicroRNA family members generally share an identical seed and differ at only a few positions overall (underlined). The mir-17–92 cluster is illustrated, demonstrating the seed (bold) as well as the high degree of similarity of family members (mir-17 and mir-20a). Note that the mir-18 sequence is similar to mir-17 and mir-20a but has a different seed sequence, indicating a different set of targets.

Figure 2. MicroRNAs Involved in Proliferation and Apoptosis

MicroRNAs commonly overexpressed in hepatobiliary cancer, such as mir-17–92 and mir-21 (black boxes), target proteins involved in apoptosis (yellow) and inhibiting cell proliferation (light yellow). In addition, E2F proteins have pleiotropic effects on proliferation and apoptosis. MicroRNAs with lower expression in hepatobiliary cancer (white boxes) target proteins that drive proliferation (light blue) or promote survival (blue). The effect is that in general, oncogenes are released and tumor suppressors silenced by microRNA dysregulation in cancer.