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IMP1 3' UTR shortening enhances metastatic burden in colorectal cancer.

ABSTRACT: The RNA-binding protein insulin-like growth factor 2 mRNA binding protein 1 (IMP1) is overexpressed in colorectal cancer (CRC); however, evidence for a direct role for IMP1 in CRC metastasis is lacking. IMP1 is regulated by let-7 microRNA, which binds in the 3' untranslated region (UTR) of the transcript. The availability of binding sites is in part controlled by alternative polyadenylation, which determines 3' UTR length. Expression of the short 3' UTR transcript (lacking all microRNA sites) results in higher protein levels and is correlated with increased proliferation. We used in vitro and in vivo model systems to test the hypothesis that the short 3' UTR isoform of IMP1 promotes CRC metastasis. Herein we demonstrate that 3' UTR shortening increases IMP1 protein expression and that this in turn enhances the metastatic burden to the liver, whereas expression of the long isoform (full length 3' UTR) does not. Increased tumor burden results from elevated tumor surface area driven by cell proliferation and cell survival mechanisms. These processes are independent of classical apoptosis pathways. Moreover, we demonstrate the shifts toward the short isoform are associated with metastasis in patient populations where IMP1-long expression predominates. Overall, our work demonstrates that different IMP1 expression levels result in different functional outcomes in CRC metastasis and that targeting IMP1 may reduce tumor progression in some patients.

SUBMITTER: Andres SF

PROVIDER: S-EPMC6556707 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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IMP1 3' UTR shortening enhances metastatic burden in colorectal cancer.

Andres Sarah F SF Williams Kathy N KN Plesset Jacqueline B JB Headd Jeffrey J JJ Mizuno Rei R Chatterji Priya P Lento Ashley A AA Klein-Szanto Andres J AJ Mick Rosemarie R Hamilton Kathryn E KE Rustgi Anil K AK

Carcinogenesis 20190601 4

The RNA-binding protein insulin-like growth factor 2 mRNA binding protein 1 (IMP1) is overexpressed in colorectal cancer (CRC); however, evidence for a direct role for IMP1 in CRC metastasis is lacking. IMP1 is regulated by let-7 microRNA, which binds in the 3' untranslated region (UTR) of the transcript. The availability of binding sites is in part controlled by alternative polyadenylation, which determines 3' UTR length. Expression of the short 3' UTR transcript (lacking all microRNA sites) re ...[more]

PMID: 30407516

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Project description:Microenvironmental factors such as non-classical human leukocyte antigen-G (HLA-G) have been associated with cancer invasiveness and metastatic progression. HLA-G expression has been associated with specific single-nucleotide polymorphisms (SNP) in HLA-G 3'untranslated region (UTR) in several diseases. The primary aim was to investigate the predictive role of HLA-G polymorphisms on treatment efficacy in metastatic colorectal cancer (mCRC) patients homogeneously treated with first-line FOLFIRI (irinotecan, 5-fluorouracil, and leucovorin) and their association with soluble HLA-G (sHLA-G) plasma concentration. HLA-G 3'UTR was sequenced in 248 patients. A set of eight polymorphisms and related haplotypes were analyzed for their association with best tumor response, overall survival (OS), and progression-free survival (PFS). sHLA-G was measured by immunoassay in 35 available plasma samples and correlated with HLA-G 3'UTR polymorphisms/haplotypes. Our results showed that carriers of rs371194629 (+2960)-Ins allele were at risk for lack of complete response (hazard ratio (HR):0.29, pBH = 0.0336), while carriers of rs1710 (+3010)-G allele (rs1063320 (+3142)-C allele in linkage-disequilibrium), and rs9380142 (+3187)-G allele had a higher chance of complete response according to additive models (HR:4.58, pBH = 0.0245; HR:3.18, pBH = 0.0336, respectively). The combination of rs371194629-Del, rs1710-G, and rs9380142-G alleles forms the UTR1 haplotype. Patients who were carriers of UTR1/UTR-1 diplotype had a greater chance of complete response to therapy (HR:10.59, pBH = 0.0294). The same three beneficial alleles showed a trend toward higher pre-treatment sHLA-G plasma levels, supporting a functional role for polymorphisms in protein secretion. In conclusion, genetic variants of HLA-G are associated with treatment efficacy in mCRC patients treated with first-line FOLFIRI. This finding shed light on the combined effect of this immune system factor and chemotherapy in cancer patients.

Project description:ImportanceThe COVID-19 pandemic has been associated with substantial reduction in screening, case identification, and hospital referrals among patients with cancer. However, no study has quantitatively examined the implications of this correlation for cancer patient management.ObjectiveTo evaluate the association of the COVID-19 pandemic lockdown with the tumor burden of patients who were diagnosed with metastatic colorectal cancer (mCRC) before vs after lockdown.Design, setting, and participantsThis cohort study analyzed participants in the screening procedure of the PANIRINOX (Phase II Randomized Study Comparing FOLFIRINOX + Panitumumab vs FOLFOX + Panitumumab in Metastatic Colorectal Cancer Patients Stratified by RAS Status from Circulating DNA Analysis) phase 2 randomized clinical trial. These newly diagnosed patients received care at 1 of 18 different clinical centers in France and were recruited before or after the lockdown was enacted in France in the spring of 2020. Patients underwent a blood-sampling screening procedure to identify their RAS and BRAF tumor status.ExposuresmCRC.Main outcomes and measuresCirculating tumor DNA (ctDNA) analysis was used to identify RAS and BRAF status. Tumor burden was evaluated by the total plasma ctDNA concentration. The median ctDNA concentration was compared in patients who underwent screening before (November 11, 2019, to March 9, 2020) vs after (May 14 to September 3, 2020) lockdown and in patients who were included from the start of the PANIRINOX study.ResultsA total of 80 patients were included, of whom 40 underwent screening before and 40 others underwent screening after the first COVID-19 lockdown in France. These patients included 48 men (60.0%) and 32 women (40.0%) and had a median (range) age of 62 (37-77) years. The median ctDNA concentration was statistically higher in patients who were newly diagnosed after lockdown compared with those who were diagnosed before lockdown (119.2 ng/mL vs 17.3 ng/mL; P < .001). Patients with mCRC and high ctDNA concentration had lower median survival compared with those with lower concentration (14.7 [95% CI, 8.8-18.0] months vs 20.0 [95% CI, 14.1-32.0] months). This finding points to the potential adverse consequences of the COVID-19 pandemic and related lockdown.Conclusions and relevanceThis cohort study found that tumor burden differed between patients who received an mCRC diagnosis before vs after the first COVID-19 lockdown in France. The findings of this study suggest that CRC is a major area for intervention to minimize pandemic-associated delays in screening, diagnosis, and treatment.

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IMP1 3' UTR shortening enhances metastatic burden in colorectal cancer.

Publications

IMP1 3' UTR shortening enhances metastatic burden in colorectal cancer.

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