Article

miR-297 modulates multidrug resistance in human colorectal carcinoma by down-regulating MRP-2.

State Key Laboratory of Bioreactor Engineering and Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, PR China.
Biochemical Journal (Impact Factor: 4.78). 06/2012; 446(2):291-300. DOI: 10.1042/BJ20120386
Source: PubMed

ABSTRACT Colorectal carcinoma is a frequent cause of cancer-related death in men and women. miRNAs (microRNAs) are endogenous small non-coding RNAs that regulate gene expression negatively at the post-transcriptional level. In the present study we investigated the possible role of microRNAs in the development of MDR (multidrug resistance) in colorectal carcinoma cells. We analysed miRNA expression levels between MDR colorectal carcinoma cell line HCT116/L-OHP cells and their parent cell line HCT116 using a miRNA microarray. miR-297 showed lower expression in HCT116/L-OHP cells compared with its parental cells. MRP-2 (MDR-associated protein 2) is an important MDR protein in platinum-drug-resistance cells and is a predicted target of miR-297. Additionally miR-297 was down-regulated in a panel of human colorectal carcinoma tissues and negatively correlated with expression levels of MRP-2. Furthermore, we found that ectopic expression of miR-297 in MDR colorectal carcinoma cells reduced MRP-2 protein level and sensitized these cells to anti-cancer drugs in vitro and in vivo. Taken together, our findings suggest that miR-297 could play a role in the development of MDR in colorectal carcinoma cells, at least in part by modulation of MRP-2.

1 Follower
 · 
172 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: MicroRNAs (miRNAs) regulate multiple molecular pathways vital for the hallmarks of cancer with a high degree of biochemical specificity and potency. By restoring tumor suppressive miRNAs or ablating oncomiRs, miRNA-based therapies can sensitize cancer cells to conventional cytotoxins and the molecularly targeted drugs by promoting apoptosis and autophagy, reverting epithelial-to-mesenchymal transition, suppressing tumor angiogenesis, and downregulating efflux transporters. The development of miRNA-based therapeutics in combination with small-molecule anticancer drugs provides an unprecedented opportunity to counteract chemoresistance and improve treatment outcome in a broad range of human cancers. This review summarizes the mechanisms and advantages for the combination therapies involving miRNAs and small-molecule drugs, as well as the recent advances in the co-delivery nanocarriers for these agents.
    Advanced Drug Delivery Reviews 10/2014; DOI:10.1016/j.addr.2014.09.010 · 12.71 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The ATP-binding cassette (ABC) transporters are members of a protein superfamily that are known to translocate various substrates across membranes, including metabolic products, lipids and sterols, and xenobiotic drugs. Multidrug resistance proteins (MRPs) belong to the subfamily C in the ABC transporter superfamily. MRPs have been implicated in mediating multidrug resistance by actively extruding chemotherapeutic substrates. Moreover, some MRPs are known to be essential in physiological excretory or regulatory pathways. The importance of MRPs in cancer therapy is also implied by their clinical insights. Modulating the function of MRPs to re-sensitize chemotherapeutic agents in cancer therapy shows great promise in cancer therapy; thus, multiple MRP inhibitors have been developed recently. This review article summarizes the structure, distribution, and physiological as well as pharmacological function of MRP1-MRP9 in cancer chemotherapy. Several novel modulators targeting MRPs in cancer therapy are also discussed.
    The AAPS Journal 04/2015; DOI:10.1208/s12248-015-9757-1 · 3.91 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Faster re-induction of heat acclimation (AC) after its decline indicates "AC memory". Our previous results revealed involvement of epigenetic mechanisms of transcriptional regulation. We hypothesized that the decline of AC (DeAC) is a period of "dormant memory" during which many processes are alerted to enable rapid re-acclimation (ReAC). Using a genome wide approach we studied the AC, DeAC and ReAC transcriptomes, to uncover hallmark pathways linked to "molecular memory" in the cardio-acclimatome. Rats subjected to heat acclimation [(34°C for 2d (AC2d) or 30d (AC30)], DeAC, (24°C, 30d), ReAC, (34°C, 2d) and untreated controls were used. The GeneChip Rat Gene 1.0 ST Array was employed for left ventricular (cardiac) mRNA hybridization. Three independent bioinformatic analyses showed that (i) during AC2d enrichment of DNA impair/repair linked genes is seen, and this is the molecular on-switch of acclimation; (ii) genes activated in AC30 underlie the qualitative physiological adaptations of cardiac performance; (iii) particular molecular programs encompassing constitutive up-regulation of P38 MAPK, JaK/stat and AKT pathways and targets are specifically activated during DeAC and ReAC; (iv) epigenetic markers such as linker histones (histones H1 cluster), associated with nucleosome spacing, transcriptional chromatin modifiers, poly-(ADP-ribose) polymerase-1 (PARP1) linked to chromatin compaction and microRNAs are only altered duringDeAC/ReAC. The latter are newcomers to the AC/DeAC puzzle. We suggest that these transcriptional responses maintain euchromatin and proteostasis and enable faster physiological recovery upon ReAC by rapidly reestablishing the protected acclimated cardiophenotype. We propose that the cardiac AC model can be applied to acclimation processes in general.
    Journal of Applied Physiology 09/2014; 117(11). DOI:10.1152/japplphysiol.00422.2014 · 3.43 Impact Factor