MicroRNA let-7a: a novel therapeutic candidate in prostate cancer.

Dear Editor,

It is known that microRNA let-7a can be useful for diagnosis and therapy of cancer, including prostate cancer (PCa).1 A recent article by Wang et al.2 comprehensively showed that let-7a1 could inhibit the expression of insulin-like growth factor-1 receptor (IGF1R) by directly targeting the T1 and T2 sites in the 3’ untranslated region (3’UTR) of IGF1R mRNA. Furthermore, they found that let-7a1-mediated IGF1R downregulation was accompanied by attenuation of Elk1 activity and c-fos expression, inhibition of PC-3 cell proliferation, cell cycle arrest and induced apoptosis and that inhibition of let-7a1 could up-regulate IGF1R accompanied by an increase of Elk1 activity and c-fos expression, thereby enhancing cell proliferation.2 Their study is interesting and provides valuable data on the role of let-7a in PCa. Another study has3, in fact, demonstrated that let-7a directly bound to the 3’UTR of E2F2 (E2F family of transcription factor) and CCND2 (cyclin D2) and downregulated their expression, leading to cell-cycle arrest at the G1/S phase and inhibit the PC-3 cells and LNCaP cells growth, especially in hormone-refractory PCa. In addition, xenograft models of PC-3 cells confirmed the capability of let-7a to inhibit prostate tumor development in vivo.3 Emerging evidences suggest that the let-7 family plays a crucial role in the progression of PCa by maintaining and regulating molecular features of cancer stem cells or cancer stem-like cells in PCa.45 Recently, Liu et al.6 showed that let-7a was underexpressed in the purified CD44 + Du145, LAPC9 and LAPC4 cells. And after they infected Du145 and LAPC9 cells with pLL3.7-let-7a, both Du145 clonal development and sphere formation were inhibited. Impressively, the continuously delivered let-7a distinctly slowed tumor growth and inhibited tumor regeneration of LAPC9 cells. However, PCa cells infected with pLL3.7-let-7a keep low steady-state levels of let-7a. This phenomenon may be explained by let-7a miRNAs, which have a fast turnover rate. Another interesting finding was that let-7a caused a prominent G2/M phase arrest without inducing senescence.6 What's more, Kong and colleagues indicated that loss of let-7 family with corresponding overexpression of enhancer of zeste homolog 2 (EZH2) contributed to human PCa aggressiveness, which could be attenuated after the formulated 3,3’-diindolylmethane (BR-DIM) invention in their ongoing phase II clinical trial in patients prior to radical prostatectomy.7

The above-described results demonstrate a genetic association between let-7a and PCa, supporting a potential role for let-7a in human PCa. A recent study showed that let-7a remained to significantly discriminate normal tissues from PCa patients from those of the cancer negative control group with elevated prostate-specific antigen levels (P < 0.05).8 In any case, reduced transcription patterns of let-7a could be considered as indicators of occult tumors in the vicinity. Furthermore, Schubert et al.9 also confirmed a significant downregulation of let-7a in the high-risk PCa cases compared to benign prostatic hyperplasia (P < 0.001). However, Pesta et al.10 found no statistical differences in expression of let-7a in the PCa tissue samples in comparison with the BPH tissue samples. They have reminded us that the behavior of BPH did not necessarily correspond with that of normal prostatic tissue.10

In summary, available evidence suggests a key role for let-7a in the development of PCa although there are differences in the samples; moreover, several target genes of let-7a are associated with PCa (). Thus, these findings indicate that let-7a may be a potential noninvasive biomarker and novel therapeutic candidate in PCa. However, the precise mechanisms of let-7a in the pathogenesis of PCa need to be elucidated. Conclusions drawn from animal model studies should be limited to animal models until they are confirmed in human PCa. Therefore, further studies are required, especially in human systems, to comprehensively explore the therapeutic potential of let-7a in PCa. The development of therapeutic agents about let-7a could result in important new innovative therapies for the treatment of PCa and other cancers.

AUTHOR CONTRIBUTIONS

XQW conceived of the study, and drafted and revised the manuscript. CH participated in the design of the study. XHL assisted with the revising of the manuscript. JL participated in its design and coordination and revision of the manuscript. All authors read and approved the final manuscript.

COMPETING INTERESTS

The authors declare no competing interests.

Table 1

The role of microRNA let-7a in prostate cancer