(A) The reduction or deletion of a “tumor suppressor miRNA” due to mutation, deletion, epigenetic modification, or irregularities in miRNA processing cause inappropriate elevation of miRNA-target oncoproteins, ultimately leading to tumor formation. (B) Amplification or overexpression of an “oncogenic miRNA” inhibits miRNA-targets of vital tumor suppressor genes. The overall outcome is to increase cell proliferation, angiogenesis, and metastasis, or augment chromosomal instability and apoptosis.

Dietary agents such as curcumin, resveratrol, DIM, I3C, EGCG, and ellagitannin modulate miRNAs that regulate cancer signaling pathways.

Pri-miRNAs are transcribed from RNA polymerase II (RNAPII)-specific miRNA genes, from the intronic region of protein coding genes, or from polycistronic transcripts. In the first nuclear step, pri-miRNA is processed into a 70–100 nucleotide precursor hairpin (pre-miRNA) via the Drosha-DGCR8 complex. Pre-miRNA is transported to the cytoplasm through export machinery consisting of Exportin 5 and Ran-GTP. Here, the pre-miRNA is cleaved by another endoribonuclease, Dicer, in partnership with TRBP and Ago proteins, forming a ~20-bp miRNA: miRNA* duplex. After processing, one strand of the duplex is preferentially incorporated with the help of Ago2 into the RISC complex (miRISC), whereas the other “passenger” strand (miRNA*) gets degraded. (A) A few pre-miRNAs are processed directly from short introns (mirtrons), bypassing the Drosha-DGCR8 step. (B) A dicer-independent mechanism, miRNA being cleaved by Ago2 to form a mature miRNA. (C) Some miRNAs bind to the 5′-UTR of the target mRNA and lead to translational activation. (D) Full or near-full complementarity between miRNA and mRNA target facilitates miRISC-directed cleavage of the mRNA target. (E) With low complementarity, miRNA-mediated regulation is carried out by translational repression (E.1). This can occur pre- and/or post-initiation of translation leading to gene silencing. (E.2) Target mRNAs also can be stored in P-bodies, and mechanism reversed by re-entry into polysomes for translation. (F) In a RISC-independent decoy activity, miRNAs can directly bind to proteins, particularly RNA-binding proteins, making them unavailable for binding to their RNA targets.

MiRNAs can impact the epigenetic machinery by regulating key players involved in DNA methylation and chromatin remodeling. (A) Demethylated tumor suppressor miR-29 (open red dots) inhibits translation of cancer-promoting DNMT3s in lung cancer, (B) Hypermethylation of let-7a-3 (closed red dots) in normal cells results in repression of cancer-promoting genes in lung, (C) An integrated loop is becoming apparent between miRNAs, and chromatin remodeling via HATs and HDACs, which influence miRNA expression in the cell.