MicroRNA-21 regulates stemness in cancer cells.

MicroRNA-21 (miR-21) functions have been linked to cancer progression and chemo- or radiotherapy resistance. While an increasing number of studies have reported a potential role of miR-21 expression in promoting growth of a small population of stem/progenitor cells, knowledge on its role as a regulator of stemness in cancers remains limited. In a previous issue of Stem Cell Research & Therapy, Chung and colleagues provide evidence that miR-21 is highly expressed in stem/progenitor populations of ovarian teratocarcinoma cells and has the potential to mediate growth and self-renewal in cancer stem/progenitor cells. Here we summarize current knowledge on miR-21 functions in human cancers and discuss how this finding provides insight into the role of miR-21 as an oncogenic regulator in stem/progenitor cell populations of human cancers.

More than 1,000 microRNAs (miRNAs/miRs) are expressed in human cells, where they participate in either pathological or physiological processes, affecting cell behavior and function and organismic phenotype. Among these, miR-21 has emerged as one of the most commonly and strongly upregulated miRs in a wide variety of human cancers. However, our understanding of the mechanisms of miR-21 elevation as a common feature in cancer remains rudimentary. The study by Chung and colleagues in a previous issue of Stem Cell Research &Therapy discovered that miR-21 promotes ovarian teratocarcinoma cell growth through sustaining cancer stem/progenitor populations [1]. Their study provides new fundamental insights into the role of miR-21 as an oncogenic regulator in stem/progenitor cell populations that is involved in the promotion of the cellular transformation process and chemotherapy resistance.

miR-21 elevation has been demonstrated in miscellaneous human cancers, including glioblastoma, liver, gastric, cervical, thyroid, breast, prostate, colorectal, lung, pancreas, skin, and various lymphatic and hematopoietic cancers [2]. Although it has been identified as the best hit in a number of medium-scale and high-scale profiling experiments designed for the detection of miRNAs dysregulated in multiple cancer types, whether miR-21 exerts its oncogenic function on stem/progenitor populations of most types of cancers remains to be further investigated. One important point derived from this publication is that the increase in miR-21 expression in cancers may come from genetic changes underlying cancer stem/progenitor populations that lead to cancer progression, and chemo- or radiotherapy resistance. In a recent review on the oncogenic function of miR-21, this concept is further supported by evidence of altered promoter methylation of miR-21 associated with gene mutations in clear cell renal cell carcinoma [3] and that overexpression of miR-21 in mice leads to pre-B lymphoma formation [4]. Recent studies also reported that miR-21 could promote the migration and invasion of a stem-like population in hepatocellular carcinoma [5,6]. As it becomes progressively more evident that miR-21 may enhance cancer stem/progenitor cell growth, it would be of interest to elucidate by which mechanism miR-21 influences progenitor cells.

There are several possible mechanisms by which miR-21 may promote cancer stem/progenitor populations: first, miR-21 in non-progenitor cancer cells could produce growth factors that enrich stem cell populations; second, miR-21 in the cancer progenitor cell niche might directly regulate progenitor cells to self-renew; third, miR-21 in certain non-progenitor cancer cells may trigger a dedifferentiation process, so enriching stem cell populations. Although a recent report showed that miR-21 expression and function are associated with chemotherapy resistance, accompanied by increasing cancer stem/progenitor populations [7], as well as enriched side population cells (stem/progenitor cells) in hepatocellular carcinoma cell lines [6], there has been no clear dissection of the function of miR-21 in stem or non-stem populations of cancer cells.

In the report by Chung and colleagues, it was shown that miR-21 could promote the growth of ovarian teratocarcinoma PA1 cells, while knockdown of miR-21 could abolish cell growth. Furthermore, by dissecting CD133+ and CD133- cancer progenitor populations, they found that miR-21-mediated self-renewal of stem/progeny cells preferentially occurred in CD133+ cells. Therefore, the data presented in the article from Chung and colleagues favors the second hypothetical mechanism - that is, that miR-21 directly impacts on the progenitor cell population to promote cancer cell growth.

During homeostasis, miR-21 has been linked to cell growth and has emerged as one of the principal regulators controlling major cell functions. High levels of miR-21 may not only be a characteristic in cancer cells but also represent a common feature of pathological cell growth. For example, miR-21 is found to be essential for rapid growth of hepatic cells during liver regeneration [8]. Transient miR-21 expression after partial hepatectomy could suppress Rhob, subsequently relieving Akt/mTOR ablating effects on eIF/4F to trigger cyclin D1 translation and thus activating the cell cycle of mouse liver cells [8]. Interestingly, miR-21 is also upregulated in several models of mouse cardiac hypertrophy and in a variety of other human proliferative disorders [9], implying a function in regulating cell growth. This idea is further supported by evidence of miR-21 induction associated with maintaining mouse spermatogonial germ cell populations [10].

The accumulating data support an appealing concept that sequence-specific inhibition of miRNAs in stem/progenitor cell populations can provide a novel therapeutic approach for modulation of stem/progenitor cells whose function is deregulated in cancer. In the study by Chung and colleagues, knockdown of miR-21 resulted in a marked reduction in the CD133+ population and sphere formation of stem/progenitor cells, thus inhibiting the growth of ovarian teratocarcinoma cells, suggesting such modulation has therapeutic potential. It is conceivable that modulation of miR-21 may sensitize stem/progenitor cells in modulating drug responses. It will be of great interest to investigate whether targeting miR-21 is one of the key approaches that enhance the susceptibility of cancer stem/progenitor cells to chemo- and radiotherapeutic treatments. In conjunction with current therapeutic regimens, this may eventually lead to an effective strategy in the fight against these deadly cancers in the near future.

Abbreviations

miRNA/miR: microRNA.

Competing interests

The author declares that they have no competing interests.