miR-21 and miR-145 cooperation in regulation of colon cancer stem cells

Molecular Cancer

Research

Sindhu G. Rajendra¹  Edi Levi¹  Lulu Farhana²  Yingjie Yu²  Pratima Nangia-Makker³  Adhip PN Majumdar³ 

[1] Department of Veterans Affairs Medical Center, 4646 John R, 48201, Detroit, MI, USA;Department of Veterans Affairs Medical Center, 4646 John R, 48201, Detroit, MI, USA;Departments of Internal Medicine, Wayne State University, 48201, Detroit, MI, USA;Department of Veterans Affairs Medical Center, 4646 John R, 48201, Detroit, MI, USA;Karmanos Cancer Center, 48201, Detroit, MI, USA;Departments of Internal Medicine, Wayne State University, 48201, Detroit, MI, USA;

关键词: Colorectal cancer;    Negative feedback;    Chemo-resistance;   

DOI  :  10.1186/s12943-015-0372-7

 received in 2014-12-03, accepted in 2015-04-22,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundAcquired drug resistance is one of the major reasons for failing cancer therapies. Although the reasons are not fully understood, they may be related to the presence of cancer stem cells (CSCs). We have reported that chemo-resistant (CR) colon cancer cells, highly enriched in CSCs, exhibit a marked up-regulation of miR-21 and that down-regulation of this miR renders the CR cells more susceptible to therapeutic regimens. However, the underlying molecular mechanism is poorly understood. The aim of this investigation is to unravel this mechanism.MethodsThe levels of miR-145 and miR-21 were manipulated by transfection of mature, antago-miRs or pCMV/miR-145 expression plasmid. Quantitative RT-PCR or/and Western blots were performed to examine the expression of CD44, β-catenin, Sox-2, PDCD4, CK-20 and k-Ras. Colonosphere formation and SCID mice xenograft studies were performed to evaluate the tumorigenic properties of CSC-enriched colon CR cells.ResultsWe investigated the role that microRNAs (miRs), specifically miR-21 and miR-145 play in regulating colon CSCs. We found the expression of miR-21 to be greatly increased and miR-145 decreased in CR colon cancer cells that are highly enriched in CSC, indicating a role for these miRNAs in regulating CSCs. In support of this, we found that whereas forced expression of miR-145 in colon cancer cells greatly inhibits CSCs and tumor growth, up-regulation of miR-21 causes an opposite phenomenon. In addition, administration of mature miR-145 or antagomir-21 (anti-sense miR-21) greatly suppresses the growth of colon cancer cell xenografts in SCID mice. This was associated with decreased expression of CD44, β-catenin, Sox-2 and induction of CK-20 indicating that administration of miR-145 or antagomir-21 decreases CSC proliferation and induces differentiation. In vitro studies further demonstrate that miR-21 negatively regulates miR-145 and vice versa. k-Ras appears to play critical role in regulation of this process, as evidenced by the fact that the absence of k-Ras in CR colon cancer cells increases miR-145 expression, suppresses miR-21, and interrupts the negative cooperation between miR-21 and miR-145.ConclusionsOur current observations suggest that miR-21, miR-145, and their networks play critical roles in regulating CSCs growth and/or differentiation in the colon cancer and progression of chemo-resistance.

【 授权许可】

CC BY   
© Yu et al.; licensee BioMed Central. 2015