MicroRNA-21 induces resistance to 5-fluorouracil by down-regulating human DNA MutS homolog 2 (hMSH2)

Valeri, Nicola; Gasparini, Pierluigi; Braconi, Chiara; Paone, Alessio; Lovat, Francesca; Fabbri, Muller; Sumani, Khlea M.; Alder, Hansjüerg; Amadori, Dino; Patel, Tushar; Nuovo, Gerard J.; Fishel, Richard; Croce, Carlo M.

doi:10.1073/pnas.1015541107

Cited by 329 publications

(261 citation statements)

References 27 publications

(30 reference statements)

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“…The other related studies almost focused on either 5-fluorouracil (Song et al, 2009;Boni et al, 2010;Valeri et al, 2010;Nishida et al, 2012) or oxaliplatin (Akao et al, 2011;Chai et al, 2011;Xu et al, 2012;Xu et al, 2013). Compared with the studies about one single agent, our work served the clinical practice better.…”

Section: Discussionmentioning

confidence: 89%

Serum miR-19a Predicts Resistance to FOLFOX Chemotherapy in Advanced Colorectal Cancer Cases

Chen¹,

Xiao²,

Ge³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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Background: Colorectal cancer is the fourth most common cancer worldwide and the second leading cause of cancer-related death. FOLFOX is the most common regimen used in the first-line chemotherapy in advanced colorectal cancer, but only half of the patients respond to this regimen and we have almost no clue in predicting resistance in such first-line application. Methods: To explore the potential molecular biomarkers predicting the resistance of FOLFOX regimen as the first-line treatment in advanced colorectal cancer, we screened microRNAs in serum samples from drug-responsive and drug-resistant patients by microarrays. Then differential microRNA expression was further validated in an independent population by reverse transcription and quantitative realtime PCR. Results: 62 microRNAs expressing differentially with fold-change >2 were screened out by microarray analysis. Among them, 5 (miR-221, miR-222, miR-122, miR-19a, miR-144) were chosen for further validation in an independent population (N=72). Our results indicated serum miR-19a to be significantly up-regulated in resistance-phase serum (p=0.009). The ROC curve analysis showed that the sensitivity of serum miR-19a to discriminate the resistant patients from the response ones was 66.7%, and the specificity was 63.9% when the AUC was 0.679. We additionally observed serum miR-19a had a complementary value for cancer embryonic antigen (CEA). Stratified analysis further revealed that serum miR-19a predicted both intrinsic and acquired drug resistance. Conclusions: Our findings confirmed aberrant expression of serum miR-19a in FOLFOX chemotherapy resistance patients, suggesting serum miR-19a could be a potential molecular biomarker for predicting and monitoring resistance to first-line FOLFOX chemotherapy regimens in advanced colorectal cancer patients.

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Section: Discussionmentioning

confidence: 89%

Serum miR-19a Predicts Resistance to FOLFOX Chemotherapy in Advanced Colorectal Cancer Cases

Chen¹,

Xiao²,

Ge³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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“…137 In addition, its expression is associated with chemoresistance in a variety of cancer cells. [138][139][140] Interestingly, miR-21 has also been described to indirectly regulate MDR-1 expression. 141 A novel hyaluronan (HA)-CD44-mediated PKC signalling mechanism which regulates a stem cell marker (Nanog) has been associated with miR-21 production.…”

Section: Mirs Acting At the Post-transcriptional Level -Direct Regulamentioning

confidence: 99%

The network of P-glycoprotein and microRNAs interactions

et al. 2013

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Overexpression of P‐glycoprotein (P‐gp) contributes to the multidrug resistance (MDR) phenotype found in many cancer cells. P‐gp has been identified as a promising molecular target, although attempts to find successful therapies to counteract its function as a drug efflux pump have largely failed to date. Apart from its role in drug efflux, P‐gp may have other cellular functions such as being involved in apoptosis, and is found in various locations in the cell. Its expression is highly regulated, namely by microRNAs (miRNAs or miRs). In addition, P‐gp may regulate the expression of miRs in the cell. Furthermore, both P‐gp and miRs may be found in microvesicles or exosomes and may be transported to neighboring, drug‐sensitive cells. Here, we review this current issue together with recent evidence of this network of interactions between P‐gp and miRs.

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“…miRNAs have been shown to regulate diverse cellular processes, including the DNA mismatch repair (MMR) pathway [12][13][14], a major genome maintenance system. The importance of MMR in genome maintenance is demonstrated by the fact that defects in the system cause genome instability and susceptibility to human cancers [15][16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, precise regulation of the cellular level of MLH1 is critical for genome stability. Although miRNAs likely play an important role in regulating MLH1 expression [12][13][14], the mechanism of the regulation reaction is unclear. Interestingly, recent studies suggest that MLH1 may modulate miRNA processing, as MLH1 expression determines miRNA expression patterns in colorectal tumors [27,28].…”

Section: Introductionmentioning

confidence: 99%

Modulation of microRNA processing by mismatch repair protein MutLα

et al. 2012

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MicroRNAs (miRNAs) are critical post-transcriptional regulators and are derived from hairpin-shaped primary transcripts via a series of processing steps. However, how the production of individual miRNAs is regulated remains largely unknown. Similarly, loss or overexpression of the key mismatch repair protein MutLα (MLH1-PMS2 heterodimer) leads to genome instability and tumorigenesis, but the mechanisms controlling MutLα expression are unknown. Here we demonstrate in vitro and in vivo that MLH1 and miR-422a participate in a feedback loop that regulates the level of both molecules. Using a defined in-vitro miRNA processing system, we show that MutLα stimulates the conversion of pri-miR-422a to pre-miR-422a, as well as the processing of other miRNAs tested, implicating MutLα as a general stimulating factor for miRNA biogenesis. This newly identified MutLα function requires its ATPase and pri-miRNA binding activities. In contrast, miR-422a downregulates MutLα levels by suppressing MLH1 expression through base pairing with the MLH1 3′-untranslated region. A model depicting this feedback mechanism is discussed.

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MicroRNA-21 induces resistance to 5-fluorouracil by down-regulating human DNA MutS homolog 2 (hMSH2)

Cited by 329 publications

References 27 publications

Serum miR-19a Predicts Resistance to FOLFOX Chemotherapy in Advanced Colorectal Cancer Cases

Serum miR-19a Predicts Resistance to FOLFOX Chemotherapy in Advanced Colorectal Cancer Cases

The network of P-glycoprotein and microRNAs interactions

Modulation of microRNA processing by mismatch repair protein MutLα

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