ABCB1/MDR1 gene polymorphism and colorectal cancer risk: a meta‐analysis of case–control studies

He, Tao; Mo, Anwei; Zhang, K.; Liu, L.

doi:10.1111/j.1463-1318.2012.02919.x

Cited by 31 publications

(28 citation statements)

References 27 publications

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“…In contrast, P-gp-deficient APC Min/+ mice develop fewer polyps in the non-inflamed small intestine than wild-type (WT) [19]. The C3435T and intron 3 (G-rs3789243-A) polymorphisms of the human ABCB1/MDR1 gene have been associated with increased risks for UC [20–22] or CRC [23–26] in some populations, but not all [24, 27, 28]. However, the precise role of ABCB1/MDR1 in CAC pathogenesis has not been delineated yet.…”

Section: Introductionmentioning

confidence: 99%

MDR1A deficiency restrains tumor growth in murine colitis-associated carcinogenesis

et al. 2017

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Patients with Ulcerative Colitis (UC) have an increased risk to develop colitis-associated colorectal cancer (CAC). Here, we found that protein expression of ABCB1 (ATP Binding Cassette Subfamily B Member 1) / MDR1 (multidrug resistance 1) was diminished in the intestinal mucosa of patients with active UC with or without CAC, but not in non-UC patients with sporadic colon cancer. We investigated the consequences of ABCB1/MDR1 loss-of-function in a common murine model for CAC (AOM/DSS). Mice deficient in MDR1A (MDR1A KO) showed enhanced intratumoral inflammation and cellular damage, which were associated with reduced colonic tumor size and decreased degree of dysplasia, when compared to wild-type (WT). Increased cell injury correlated with reduced capacity for growth of MDR1A KO tumor spheroids cultured ex-vivo. Gene expression analysis by microarray demonstrated that MDR1A deficiency shaped the inflammatory response towards an anti-tumorigenic microenvironment by downregulating genes known to be important mediators of cancer progression (PTGS2 (COX2), EREG, IL-11). MDR1A KO tumors showed increased gene expression of TNFSF10 (TRAIL), a known inducer of cancer cell death, and CCL12, a strong trigger of B cell chemotaxis. Abundant B220+ B lymphocyte infiltrates with interspersed CD138+ plasma cells were recruited to the MDR1A KO tumor microenvironment, concomitant with high levels of immunoglobulin light chain genes. In contrast, MDR1A deficiency in RAG2 KO mice that lack both B and T cells aggravated colonic tumor progression. MDR1A KO CD19+ B cells, but not WT CD19+ B cells, suppressed growth of colonic tumor-derived spheroids from AOM/DSS-WT mice in an ex-vivo co-culture system, implying that B-cell regulated immune responses contributed to delayed tumor development in MDR1A deficiency. In conclusion, we provide first evidence that loss of ABCB1/MDR1 function may represent an essential tumor-suppressive host defense mechanism in CAC.

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Section: Introductionmentioning

confidence: 99%

MDR1A deficiency restrains tumor growth in murine colitis-associated carcinogenesis

et al. 2017

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“…Increasing body of evidence indicates that the ABC transporter family is irreplaceable in acquired chemoresistance, and the most important one is the ABCB1 family, encoding MDR1 (P-gp) protein (22)(23)(24). Therefore we assessed whether MDR1 was involved in cisplatin-induced chemoresistance in our study.…”

Section: Cisplatin Treatment Induces Elevated Expression Of Mdr1 (P-gmentioning

confidence: 99%

HIF-1α/MDR1 pathway confers chemoresistance to cisplatin in bladder cancer

et al. 2015

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Abstract. Bladder cancer (BCa) is the 9th most common malignant tumor and the 13th leading cause of death due to cancer. The development of surgery and target drugs bring new challenges for the traditional concept for BCa therapy, and chemotherapy is still the final option for many BCa patients, and cisplatin-containing regimen the most effective one. However, the ubiquitous application of cisplatin-containing regimen in BCa results in the cisplatin-resistance, in addition, the cisplatin-resistant BCa manifests enhanced malignant behavior, the mechanism of which is unclear. In the present study, we used BCa cell lines to to clarify this point. BCa cell lines T24/J82 were pretreated with cisplatin >3 months to construct stable cisplatin-resistant cell lines (tagged T24Cis-R and J82Cis-R ), which manifested as enhanced capacity of proliferation and malignant behavior in vivo and in vitro, accompanied by cisplatin, and even doxorubicin resistance. The following mechanism dissection revealed that prolonged treatment time of T24/J82 cells led to elevated expression of HIF-1α, which targeted the increased expression of MDR1 on the one hand, and contributed to BCa cell proliferation, migration/invasion on the other hand. Finally, IHC staining of human BCa tissue supported our conclusion that the expression of HIF-1α and MDR1 was higher in chemoresistant tissue vs. chemosensitive tissue. Our results provided a new view of HIF-1α in chemotherapy.

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“…Although 5-FU is not a substrate of MDR1 protein, there’s some, albeit controversial evidence that SNPs within the ABCB1 gene, may be associated with CRC risk [62], [63]. Nonetheless, the SNP rs17160359 (ABCB1, 5UR/G-4254T) which is implicated in the multivariate model to be associated with drug response in CRC patient, resides in the promoter region and the T allele of the SNP creates a binding site of a transcription factor called HMGA1 which is expressed at very low level in adult human tissues but highly expressed in various tumours [64].…”

Section: Resultsmentioning

confidence: 99%

Potentially Functional SNPs (pfSNPs) as Novel Genomic Predictors of 5-FU Response in Metastatic Colorectal Cancer Patients

Wang

Zhao

et al. 2014

PLoS ONE

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5-Fluorouracil (5-FU) and its pro-drug Capecitabine have been widely used in treating colorectal cancer. However, not all patients will respond to the drug, hence there is a need to develop reliable early predictive biomarkers for 5-FU response. Here, we report a novel potentially functional Single Nucleotide Polymorphism (pfSNP) approach to identify SNPs that may serve as predictive biomarkers of response to 5-FU in Chinese metastatic colorectal cancer (CRC) patients. 1547 pfSNPs and one variable number tandem repeat (VNTR) in 139 genes in 5-FU drug (both PK and PD pathway) and colorectal cancer disease pathways were examined in 2 groups of CRC patients. Shrinkage of liver metastasis measured by RECIST criteria was used as the clinical end point. Four non-responder-specific pfSNPs were found to account for 37.5% of all non-responders (P<0.0003). Five additional pfSNPs were identified from a multivariate model (AUC under ROC = 0.875) that was applied for all other pfSNPs, excluding the non-responder-specific pfSNPs. These pfSNPs, which can differentiate the other non-responders from responders, mainly reside in tumor suppressor genes or genes implicated in colorectal cancer risk. Hence, a total of 9 novel SNPs with potential functional significance may be able to distinguish non-responders from responders to 5-FU. These pfSNPs may be useful biomarkers for predicting response to 5-FU.

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ABCB1/MDR1 gene polymorphism and colorectal cancer risk: a meta‐analysis of case–control studies

Cited by 31 publications

References 27 publications

MDR1A deficiency restrains tumor growth in murine colitis-associated carcinogenesis

MDR1A deficiency restrains tumor growth in murine colitis-associated carcinogenesis

HIF-1α/MDR1 pathway confers chemoresistance to cisplatin in bladder cancer

Potentially Functional SNPs (pfSNPs) as Novel Genomic Predictors of 5-FU Response in Metastatic Colorectal Cancer Patients

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