Comment on ‘MicroRNA-214 suppresses growth, migration and invasion through a novel target, high mobility group AT-hook 1, in human cervical and colorectal cancer cells’


We have read with great interest the recently published manuscript by Chandrasekaran et al (2016) about the significance of miR-214 in colorectal cancer (CRC). The authors identified high mobility group AT-hook 1 (HMGA1) as a novel direct target of miR-214 and found that low miR-214 levels correlates with high HMGA1 expression in CRC tissues. Moreover, they showed that ectopic miR-214 expression or HMGA silencing led to reduced in vitro proliferation, migration and invasion abilities in CRC cells. Although these findings are interesting and of potential importance, there are several limitations in this study that the reader should be taken into account to interpret the conclusions.

Thus, the authors demonstrated by luciferase assays that HMGA1 is a direct miR.-214 target. However, they failed to show by western blot a proper HMGA1 decrease after miR-214 overexpression in the CRC cell lines SW480 and SW620, only obtaining 11% and 7% HMGA1 reduction, respectively. This observation is probably because HMGA1 has been reported to be a target of several microRNAs in human cancer (Kaddar et al, 2009; Wei et al, 2011; D'Angelo et al, 2012; Lau et al, 2012; Lin et al, 2013; Schubert et al, 2013; Xu et al, 2014; Zhang et al, 2016; Zhou et al, 2016), some of those deregulated in CRC, which could be contributing to modulate HMGA1 expression.

Furthermore, the experimental results provided do not permit to claim that the observed antitumor effects after ectopic miR-214 expression are due to its role as HMGA1 regulator. Of note, the similar results described by Chandrasekaran et al (2016) in their manuscript could be explained by the fact that HMGA1 positively regulates the Wnt/β-catenin pathway by increasing the β-catenin-TCF4 complex formation (Xing et al, 2014). Interestingly, miR-214 has also been reported to modulate the Wnt/β-catenin pathway targeting β-catenin directly or indirectly through EZH2 (Xia et al, 2012). To demonstrate that miR-214 exerts its effects through a negative HMGA1 regulation it would be desirable to ectopic express miR-214 in CRC cells ectopically expressing HMGA1 and after its silencing.

Another relevant issue is that there are contradictory data in the literature regarding the HMGA1 status in CRC patients. The work by Liang et al (2013) reported that HMGA1 levels are reduced in CRC samples compared with adjacent normal mucosa. However, other studies highlight that HMGA1 contributes to CRC carcinogenesis and serves as a marker of poor prognosis and CRC progression to metastatic disease (Takahashi et al, 2013; Xing et al, 2014; Williams et al, 2015). Unfortunately, Chandrasekaran et al (2016) only analyzed HMGA1 in CRC samples at the mRNA level. Considering the number of microRNAs involved in HMGA1 regulation and that only a perfect match between the microRNA and its target leads to mRNA degradation, one would not expect a good correlation between HMGA1 mRNA and protein levels. This mRNA-protein correlation for HMGA1 was not analyzed in their work, and then only the evaluation of HMGA1 at the protein levels could have helped to clarify its status in CRC patients. Additionally, it woculd also be of interest to know the clinical and molecular characteristics of the patient cohort included in this study.

In conclusion, HMGA1 is under a complex regulation involving several different microRNAs, and miR-214 alone does not seem to be able to exert enough changes in HMGA1 expression to sustain that its biological significance is due to this effect. Further studies are needed to fully clarify the role of miR-214 and the HMGA1 status in CRC, and evaluate their potential therapeutic value as novel molecular targets in this disease.


  1. Chandrasekaran KS, Sathyanarayanan A, Karunagaran D (2016) MicroRNA-214 suppresses growth, migration and invasion through a novel target, high mobility group AT-hook 1, in human cervical and colorectal cancer cells. Br J Cancer 115 (6): 741–751.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. D'Angelo D, Palmieri D, Mussnich P, Roche M, Wierinckx A, Raverot G, Fedele M, Croce CM, Trouillas J, Fusco A (2012) Altered microRNA expression profile in human pituitary GH adenomas: down-regulation of miRNA targeting HMGA1, HMGA2, and E2F1. J Clin Endocrinol Metab 97 (7): E1128–E1138.

    CAS  Article  PubMed  Google Scholar 

  3. Kaddar T, Rouault JP, Chien WW, Chebel A, Gadoux M, Salles G, Ffrench M, Magaud JP (2009) Two new miR-16 targets: caprin-1 and HMGA1, proteins implicated in cell proliferation. Biol Cell 101 (9): 511–524.

    CAS  Article  Google Scholar 

  4. Lau KM, Chan QK, Pang JC, Ma FM, Li KK, Yeung WW, Cheng AS, Feng H, Chung NY, Li HM, Zhou L, Wang Y, Mao Y, Ng HK (2012) Overexpression of HMGA1 deregulates tumor growth via cdc25A and alters migration/invasion through a cdc25A-independent pathway in medulloblastoma. Acta Neuropathol 123 (4): 553–571.

    CAS  Article  PubMed  Google Scholar 

  5. Liang L, Li X, Zhang X, Lv Z, He G, Zhao W, Ren X, Li Y, Bian X, Liao W, Liu W, Yang G, Ding Y (2013) MicroRNA-137, an HMGA1 target, suppresses colorectal cancer cell invasion and metastasis in mice by directly targeting FMNL2. Gastroenterology 144 (3): 624–635.e4.

    CAS  Article  Google Scholar 

  6. Lin Y, Chen H, Hu Z, Mao Y, Xu X, Zhu Y, Xu X, Wu J, Li S, Mao Q, Zheng X, Xie L (2013) miR-26a inhibits proliferation and motility in bladder cancer by targeting HMGA1. FEBS Lett 587 (15): 2467–2473.

    CAS  Article  Google Scholar 

  7. Schubert M, Spahn M, Kneitz S, Scholz CJ, Joniau S, Stroebel P, Riedmiller H, Kneitz B (2013) Distinct microRNA expression profile in prostate cancer patients with early clinical failure and the impact of let-7 as prognostic marker in high-risk prostate cancer. PLoS One 8 (6): e65064.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. Takahashi Y, Sawada G, Sato T, Kurashige J, Mima K, Matsumura T, Uchi R, Ueo H, Ishibashi M, Takano Y, Akiyoshi S, Eguchi H, Sudo T, Sugimachi K, Tanaka J, Kudo SE, Doki Y, Mori M, Mimori K (2013) Microarray analysis reveals that high mobility group A1 is involved in colorectal cancer metastasis. Oncol Rep 30 (3): 1488–1496.

    CAS  Article  Google Scholar 

  9. Wei JJ, Wu X, Peng Y, Shi G, Basturk O, Yang X, Daniels G, Osman I, Ouyang J, Hernando E, Pellicer A, Rhim JS, Melamed J, Lee P (2011) Regulation of HMGA1 expression by microRNA-296 affects prostate cancer growth and invasion. Clin Cancer Res 17 (6): 1297–1305.

    CAS  Article  Google Scholar 

  10. Williams MD, Zhang X, Belton AS, Xian L, Huso T, Park JJ, Siems WF, Gang DR, Resar LM, Reeves R, Hill HH Jr. (2015) HMGA1 drives metabolic reprogramming of intestinal epithelium during hyperproliferation, polyposis, and colorectal carcinogenesis. J Proteome Res 14 (3): 1420–1431.

    CAS  Article  PubMed  Google Scholar 

  11. Xia H, Ooi LL, Hui KM (2012) MiR-214 targets β-catenin pathway to suppress invasion, stem-like traits and recurrence of human hepatocellular carcinoma. PLoS One 7 (9): e44206.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. Xing J, Cao G, Fu C (2014) HMGA1 interacts with β-catenin to positively regulate Wnt/β-catenin signaling in colorectal cancercells. Pathol Oncol Res 20 (4): 847–851.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. Xu G, Wang J, Jia Y, Shen F, Han W, Kang Y (2014) MiR-142-3p functions as a potential tumor suppressor in human osteosarcoma by targeting HMGA1. Cell Physiol Biochem 33 (5): 1329–1339.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. Zhang X, Tao T, Liu C, Guan H, Huang Y, Xu B, Chen M (2016) Downregulation of miR-195 promotes prostate cancer progression by targeting HMGA1. Oncol Rep 36 (1): 376–382.

    CAS  Article  PubMed  Google Scholar 

  15. Zhou WB, Zhong CN, Luo XP, Zhang YY, Zhang GY, Zhou DX, Liu LP (2016) miR-625 suppresses cell proliferation and migration by targeting HMGA1 in breast cancer. Biochem Biophys Res Commun 470 (4): 838–844.

    CAS  Article  PubMed  Google Scholar 

Download references


This work was supported by PT13/0010/0012, PI13/02609 and PI15/00934 grants from ‘Instituto de Salud Carlos III FEDER’. B. Torrejón is supported by ‘Fundación Conchita Rábago de Jiménez Díaz’.

Author information



Corresponding authors

Correspondence to Ion Cristóbal or Jesús García-Foncillas.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

This work is published under the BJC's standard license to publish agreement. After 12 months the license terms will change to a Creative Commons AttributionNonCommercial-Share Alike 4.0 Unported License.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Cristóbal, I., Torrejón, B., Madoz-Gúrpide, J. et al. Comment on ‘MicroRNA-214 suppresses growth, migration and invasion through a novel target, high mobility group AT-hook 1, in human cervical and colorectal cancer cells’. Br J Cancer 116, e7 (2017).

Download citation