MicroRNA regulation of K-Ras in pancreatic cancer and opportunities for therapeutic intervention

Abstract

The Ras family of GTPases is involved in cell proliferation, cell survival, and angiogenesis. It is upregulated in several cancers, including pancreatic cancer (PC) and leads to uncontrolled growth and aggressiveness. PC is well known to be a lethal disease with poor prognosis, plagued by limited therapeutic modalities. MicroRNAs (miRNAs), which are short non-coding RNA molecules, have recently emerged as regulators of signaling networks and have shown potential to target pathway components for therapeutic use in several malignancies. K-Ras mutations are widespread in PC cases (90%), with mutations detectable as early as pancreatic intraepithelial neoplasias and in later metastatic stages alike; therefore, these mutations in K-Ras are obvious drivers and potential targets for PC therapy. Several K-Ras targeting miRNAs have lately been discovered, and many of them have shown promise in combating pancreatic tumor growth in vitro and in mouse models. However, the field of miRNA therapy is still in its infancy, and miRNA mimics or anti-miRNA oligonucleotides that target Ras pathway have thus far not been evaluated in PC patients. In this review, we summarize the role of several miRNAs that regulate oncogenic K-Ras signaling in PC, with their prospective roles as therapeutic agents for targeting K-Ras pathway.

Effects of MIR143 on rat sarcoma signaling networks in solid tumors: A brief overview

“…Pancreatic cancer (PC) is very aggressive cancer with a poor prognosis, and, as mentioned above, a KRAS mutation is frequently observed in PC 41,43 . The downregulation of MIR143‐3p results in the activation of KRAS signaling networks, which implies an association between MIR143‐3p and RAS in PC cells 41 .…”

“…Regarding RAS signaling networks, MIR143‐3p exerts its anti–tumor effects in various human cancers by targeting RAS and its effector signaling genes, such as AKT and ERK 12,40‐42 (Figure 2, Table 1). MAPK/ERK pathways and PI3K/AKT pathways are critical pathways for the survival and proliferation of cancer cells.…”

“…Pancreatic cancer (PC) is very aggressive cancer with a poor prognosis, and, as mentioned above, a KRAS mutation is frequently observed in PC 41,43 . The downregulation of MIR143‐3p results in the activation of KRAS signaling networks, which implies an association between MIR143‐3p and RAS in PC cells 41 . Hu et al showed that the ectopic expression of MIR143 reduces the expression level of KRAS in PC cell lines and, consequently, inhibits the cell invasion, migration and metastasis 44 .…”

miR‐4324‐RACGAP1‐STAT3‐ESR1 feedback loop inhibits proliferation and metastasis of bladder cancer

“…Therapeutic failure and poor survival in BCa are attributed to its hyperproliferation and early metastasis . MicroRNAs (miRNA) are small, noncoding RNA molecules that have been reported to play important roles in BCa carcinogenesis by influencing multiple cellular processes, including proliferation, metastasis, radiation sensitivity and chemo‐sensitivity . miRNAs can negatively regulate gene expression through a variety of mechanisms, acting as tumor suppressors or oncogenes …”

“…2 MicroRNAs (miRNA) are small, noncoding RNA molecules that have been reported to play important roles in BCa carcinogenesis by influencing multiple cellular processes, including proliferation, metastasis, radiation sensitivity and chemo-sensitivity. [3][4][5] miR-NAs can negatively regulate gene expression through a variety of mechanisms, acting as tumor suppressors or oncogenes. [6][7][8] In the present study, we demonstrated for the first time that miR-4324 was significantly downregulated in BCa, and miR-4324 suppressed important traits in BCa cells, including cell proliferation, metastasis and chemo-resistance.…”