Mol Med Rep. 2013 Feb;7(2):559-64. doi: 10.3892/mmr.2012.1214.

MicroRNA-18a upregulates autophagy and ataxia telangiectasia mutated gene expression in HCT116 colon cancer cells.

Qased AB, Yi H, Liang N, Ma S, Qiao S, Liu X.

Department of Surgery, College of Medicine, University of Mosul, Mosul, Iraq.



Autophagy is an evolutionarily conserved, multi-step lysosomal degradation process in which a cell degrades its own long-lived proteins and damaged organelles. Ataxia telangiectasia mutated (ATM) has recently been shown to upregulate the process of autophagy. Previous studies showed that certain microRNAs, including miR-18a, potentially regulate ATM in cancer cells. However, the mechanisms behind the modulation of ATM by miR-18a remain to be elucidated in colon cancer cells. In the present study, we explored the impact of miR-18a on the autophagy process and ATM expression in HCT116 colon cancer cells. To determine whether a preliminary link exists between autophagy and miR-18a, HCT116 cells were irradiated and quantitative (q) PCR was performed to measure miR-18a expression. HCT116 cells were transfected with an miR-18a mimic to study its impact on indicators of autophagy. Western blotting and luciferase assays were implemented to explore the impact of miR-18a on ATM gene expression in HCT116 cells. The results showed that miR-18a expression was strongly stimulated by radiation. Ectopic overexpression of miR-18a in HCT116 cell lines potently enhanced autophagy and ionizing radiation-induced autophagy. Moreover, miR-18a overexpression led to the upregulation of ATM expression and suppression of mTORC1 activity. Results of the present study pertaining to the role of miR-18a in regulating autophagy and ATM gene expression in colon cancer cells revealed a novel function for miR-18a in a critical cellular event and on a crucial gene with significant impacts in cancer development, progression, treatment and in other diseases.

PMID: 23229340



Combating cancer via microRNAs on one hand and autophagy on the other hand is a very recent and promising field of research. Our finding that miR-18a could regulate basal and ionizing radiation-induced autophagy, at least partially through ATM gene, could explain the upstream signaling of ATM-mTOR pathway in ionizing radiation-induced autophagy ( Liang N et al, 2013).

The unique aspect about miR-18a is that it could up-regulate its tumor suppressor target gene (ATM) and a potentially tumor suppressing mechanism (autophagy) in colon cancer cells. ATM suppresses colon cancer initiation and progression via stimulating DNA repair machinery and apoptosis. The role of autophagy in colon cancer cell death is still controversial; there are many reports which stated that autophagy promotion could be utilized to improve radiosensitivity and chemosensitivity of colon cancer cells. Interestingly, it has been recently reported that miR-18a could promote apoptosis via autophagolysosomal degradation of the oncogenic hnRNP A1protein to suppress colon cancer progression in vitro (Fujiya M et al, 2013). Such findings could explain the cross-talk between autophagy and apoptosis at the microRNA level. NEDD9 (also named HEF1) and CDK19 (also known as CDC2L6) modulate Wnt/β-catenin signaling pathway to promote colon cancer progression. Humphreys et al reported recently that miRNA-18a could target and suppress the expression of NEDD9 and CDK19 oncogenes in colon cancer. miR-18a belongs to the oncogenic cluster miR-17-92 which encodes six microRNAs :miR-17, miR-18a, miR-19a, miR-20a, miR-19, and miR-92. The same study showed that overexpression of miR-18a alone could significantly suppress colon cancer cell growth while overexpression of all other members of miR-17-92 cluster could induce colon cancer growth (Humphreys K J et al. 2012). Especially miR-92 has been found to very highly expressed and play the major oncogenic member in the cluster (Tsuchida A, ‎2011). Taken together, this suggests that miR-18a may possess homeostatic function by up-regulating autophagy, apoptosis, ATM gene and down-regulating the oncogenes HEF1 and CDK19 to eventually oppose the oncogenic effect of miR-17-92 cluster in colon cancer. How do colon cancer cells overexpress the oncogene miR-92 very highly and express the tumor suppressor miR-18a mildly, it is possible that colon cancer progression is associated with selection against miR-18a expression. Indeed, future studies will uncover the underlying reason about this predilection in colon cancer similar to what has been shown about differential expression of miR-17-92 cluster members in breast cancer brought about estrogen overexpression (Castellano L, 2009).

Moreover, since we found that miR-18a expression was strongly elevated by exposure of colon cancer cell to ionizing radiation, which is considered a potent carcinogen, it could be possible that miR-18a constitutes part of body barrier again colon cancer initiation and progression as depicted in figure below.

Overall it seems that miR-18a has the upper hand over the two major programmed cell death mechanisms; autophagy and apoptosis in colon cancer. Noteworthy is that ATM loss has been linked to poor overall survival in patients receiving adjuvant therapy compared to ATM positive colon cancer patients (Beggs AD, 2012). Therefore up-regulating ATM plus cancer cell killing could be performed by introducing lentiviral delivered (in situ) miR-18a as microRNA replacement therapy or adjuvant therapy. Moreover, combination therapy of miR-18a with other colon cancer suppressing microRNAs especially miR-34a is worth further trial. In such approaches we could revolutionize colon cancer therapy in the future and with better overall survival and prognosis.

ABU BAKER QASED-fig1Hypothetical mechanism of miR-18a acting as part of body barrier against colon cancer initiation and progression.



Dr. Abu Baker Qased, PhD

Dept. of Surgery

Mosul Medical college,

University of Mosul, Mosul, IRAQ




  1. Liang N, Jia L, Liu Y, et al. ATM pathway is essential for ionizing radiation-induced autophagy, Cellular Signalling (2013).
  2. Fujiya M, Konishi H, Kamel M, et al. microRNA-18a induces apoptosis in colon cancer cells via the autophagolysosomal degradation of oncogenic heterogeneous nuclear ribonucleoprotein A1, Oncogene (2013).
  3. Humphreys KJ, Cobiac L, Richard K, et al. Histone deacetylase inhibition in colorectal cancer cells reveals competing roles for members of the oncogenic miR-17-92 cluster, Molecular carcinogenesis (2013).
  4. Tsuchida A, Ohno S, Wu W, et al. miR-92 is a key oncogenic component of the miR-17–92 cluster in colon cancer, Cancer science(2011).
  5. Castellano L, Giamas G, Jacob J. The estrogen receptor-alpha-induced microRNA signature regulates itself and its transcriptional response, PNAS(2009).
  6. Begs AD, Domingo E, McGregor M. Loss of expression of the double strand break repair protein ATM is associated with worse prognosis in colorectal cancer and loss of Ku70 expression is associated with CIN, Oncotarget(2012).
Multiselect Ultimate Query Plugin by InoPlugs Web Design Vienna | Webdesign Wien and Juwelier SchönmannMultiselect Ultimate Query Plugin by InoPlugs Web Design Vienna | Webdesign Wien and Juwelier Schönmann