MicroRNA-34a: Potent Tumor Suppressor, Cancer Stem Cell Inhibitor, and Potential Anticancer Therapeutic

Abstract

Overwhelming evidence indicates that virtually all treatment-naive tumors contain a subpopulation of cancer cells that possess some stem cell traits and properties and are operationally defined as cancer cell stem cells (CSCs). CSCs manifest inherent heterogeneity in that they may exist in an epithelial and proliferative state or a mesenchymal non-proliferative and invasive state. Spontaneous tumor progression, therapeutic treatments, and (epi)genetic mutations may also induce plasticity in non-CSCs and reprogram them into stem-like cancer cells. Intrinsic cancer cell heterogeneity and induced cancer cell plasticity, constantly and dynamically, generate a pool of CSC subpopulations with varying levels of epigenomic stability and stemness. Despite the dynamic and transient nature of CSCs, they play fundamental roles in mediating therapy resistance and tumor relapse. It is now clear that the stemness of CSCs is coordinately regulated by genetic factors and epigenetic mechanisms. Here, in this perspective, we first provide a brief updated overview of CSCs. We then focus on microRNA-34a (miR-34a), a tumor-suppressive microRNA (miRNA) devoid in many CSCs and advanced tumors. Being a member of the miR-34 family, miR-34a was identified as a p53 target in 2007. It is a bona fide tumor suppressor, and its expression is dysregulated and downregulated in various human cancers. By targeting stemness factors such as NOTCH, MYC, BCL-2, and CD44, miR-34a epigenetically and negatively regulates the functional properties of CSCs. We shall briefly discuss potential reasons behind the failure of the first-in-class clinical trial of MRX34, a liposomal miR-34a mimic. Finally, we offer several clinical settings where miR-34a can potentially be deployed to therapeutically target CSCs and advanced, therapy-resistant, and p53-mutant tumors in order to overcome therapy resistance and curb tumor relapse.

Small extracellular vesicle non-coding RNAs in pancreatic cancer: molecular mechanisms and clinical implications

“…In 2016, a Phase I clinical trial (NCT01829971) investigating MRX34, a miRNA-34a-mimic administered in a liposomal formulation, was prematurely terminated due to immune-mediated toxicity that resulted in the death of four patients [187]. Researchers have since evaluated how the safety of miR-34a-mimics as cancer therapeutics could be improved, generally commending their potential as tumor-suppressors [224]. In that matter, immunogenicity of delivery vehicles and efficient delivery to the tumor tissue have been identified as key challenges that need to be addressed [224].…”

“…Researchers have since evaluated how the safety of miR-34a-mimics as cancer therapeutics could be improved, generally commending their potential as tumor-suppressors [224]. In that matter, immunogenicity of delivery vehicles and efficient delivery to the tumor tissue have been identified as key challenges that need to be addressed [224]. Notably, Zuo et al recently utilized sEVs instead of liposomes for miR-34a delivery to PC cells, yielding promising anti-tumor activity in a preclinical setting, potentially paving the way for further studies on miR-34a as a novel therapeutic in PDAC [207].…”

Role of non-coding RNAs in tumor progression and metastasis in pancreatic cancer

“…H19 also sequesters let-7a and interferes with its ability to inhibit HMGA2-mediated EMT program [27]. miR-34a is a potent tumor suppressive miRNA that can concomitantly inhibit expression of several proto-oncogenic genes (e.g., BCL2 and c-MET) and signaling pathways (e.g., NOTCH, WNT) [79]. lncRNA HOTAIR sequesters miR-34a and leads to activation of JAK2/STAT3 signaling pathway [77].…”

Changes in Stem Cell Regulation and Epithelial Organisation during Carcinogenesis and Disease Progression in Gynaecological Malignancies

“…In addition to a necessary focus on cancer driving genes and developmental pathways which control epithelial homeostasis, it is becoming clear that micro-RNAs and noncoding RNAs could regulate CSC potential on a post-transcriptional level. Micro-RNA family miR-34 has been described in several malignancies as tumour-suppressive and thus could be a promising pharmacological therapeutic candidate [78]. As TP53 is the main regulator of miR-34 expression, this could be of great interest for HGSOC treatment [79].…”