The association between the expression of solute carrier transporters and the prognosis of pancreatic cancer

Mohelníková-Duchoňová, Beatrice; Brynychová, Veronika; Hlaváč, Viktor; Kočík, Matěj; Oliverius, Martin; Hlavsa, Jan; Honsová, Eva; Mazanec, Jan; Kala, Zdeněk; Melichar, Bohuslav; Souček, Pavel

doi:10.1007/s00280-013-2246-2

Cited by 60 publications

(51 citation statements)

References 41 publications

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“…Mutations in SLC22A18 are associated with Wilms tumour, adrenocortical carcinoma, rhabdomyosarcoma and Beckwith–Wiedemann syndrome, all pointing to potential function of the transporter as a tumour suppressor. In contrast, studies in pancreatic cancer and lung cancer have indicated the opposite, suggesting a tumour-promoting role rather than a tumour suppressor role [101,102]. Lack of information on the in vivo function of the transporter and on the identity of its physiological substrates hinders progression in our understanding of the relevance of the transporter to cancer.…”

Section: Slc22a18mentioning

confidence: 99%

SLC transporters as a novel class of tumour suppressors: identity, function and molecular mechanisms

Bhutia

Babu

Ramachandran

et al. 2016

Biochemical Journal

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The role of plasma membrane transporters in cancer is receiving increasing attention in recent years. Several transporters for essential nutrients are up-regulated in cancer and serve as tumour promoters. Transporters could also function as tumour suppressors. To date, four transporters belonging to the SLC gene family have been identified as tumour suppressors. SLC5A8 is a Na+-coupled transporter for monocarboxylates. Among its substrates are the bacterial fermentation products butyrate and propionate and the ubiquitous metabolite pyruvate. The tumour-suppressive function of this transporter relates to the ability of butyrate, propionate and pyruvate to inhibit histone deacetylases (HDAC). SLC5A8 functions as a tumour suppressor in most tissues studied thus far, and provides a molecular link to Warburg effect, a characteristic feature in most cancers. It also links colonic bacteria and dietary fibre to the host. SLC26A3 as a tumour suppressor is restricted to colon; it is a Cl-/HCO3- exchanger, facilitating the efflux of HCO3-. The likely mechanism for the tumour-suppressive function of SLC26A3 is related to intracellular pH regulation. SLC39A1 is a Zn2+ transporter and its role in tumour suppression has been shown in prostate. Zn2+ is present at high concentrations in normal prostate where it elicits its tumour-suppressive function. SLC22A18 is possibly an organic cation transporter, but the identity of its physiological substrates is unknown. As such, there is no information on molecular pathways responsible for the tumour-suppressive function of this transporter. It is likely that additional SLC transporters will be discovered as tumour suppressors in the future.

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Section: Slc22a18mentioning

confidence: 99%

SLC transporters as a novel class of tumour suppressors: identity, function and molecular mechanisms

Bhutia

Babu

Ramachandran

et al. 2016

Biochemical Journal

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“…The second goal of this study was to assess whether genetic variability in SLC22A3 associates with major clinical characteristics of PDAC considering our previously reported association of intratumoral SLC22A3 gene expression with overall survival of PDAC patients10. In the discovery phase, the number of carriers of the T allele or heterozygous genotype in rs7758229 was significantly higher in patients with metastatic disease than in those without distant metastases (OR = 3.63, 95% CI = 1.46–9.06, p = 0.006 for heterozygotes compared with the GG genotype carriers and OR = 2.76, 95% CI = 1.20–6.32, p = 0.016 for T allele carriers compared with the GG genotype carriers, Table 4).…”

Section: Resultsmentioning

confidence: 99%

“…Our recent study revealed a highly significant upregulation of SLC22A3 transcripts in PDAC tumors compared with non-neoplastic tissues10. Moreover, a high level of SLC22A3 mRNA in tumors strongly predicted a longer overall survival ( P = 0.004) in chemotherapy-treated patients.…”

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confidence: 77%

SLC22A3 polymorphisms do not modify pancreatic cancer risk, but may influence overall patient survival

Mohelníková-Duchoňová

Strouhal

Hughes

et al. 2017

Sci Rep

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Expression of the solute carrier (SLC) transporter SLC22A3 gene is associated with overall survival of pancreatic cancer patients. This study tested whether genetic variability in SLC22A3 associates with pancreatic cancer risk and prognosis. Twenty four single nucleotide polymorphisms (SNPs) tagging the SLC22A3 gene sequence and regulatory elements were selected for analysis. Of these, 22 were successfully evaluated in the discovery phase while six significant or suggestive variants entered the validation phase, comprising a total study number of 1,518 cases and 3,908 controls. In the discovery phase, rs2504938, rs9364554, and rs2457571 SNPs were significantly associated with pancreatic cancer risk. Moreover, rs7758229 associated with the presence of distant metastases, while rs512077 and rs2504956 correlated with overall survival of patients. Although replicated, the association for rs9364554 did not pass multiple testing corrections in the validation phase. Contrary to the discovery stage, rs2504938 associated with survival in the validation cohort, which was more pronounced in stage IV patients. In conclusion, common variation in the SLC22A3 gene is unlikely to significantly contribute to pancreatic cancer risk. The rs2504938 SNP in SLC22A3 significantly associates with an unfavorable prognosis of pancreatic cancer patients. Further investigation of this SNP effect on the molecular and clinical phenotype is warranted.

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“…Downregulation of OCT1 might lead to a worse or lacking response towards platin treatment. Beatrice Mohelnikova-Duchonova et al [37] also found OCT1 was downregulated in PC, which was associated with angioinvasion. Yet, this study was limited to PC patients who underwent surgery.…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 98%

“…Moreover, OCT1is expressed in liver cancer cell lines and the downregulation of OCT1 is associate with tumour progression and a worse patient survival [36]. OCT1 is also expressed in PC and the downregulation of OCT1 is related to angioinvasion [37]. In future studies, we should investigate the relationship between OCTs and PC that is treated with metformin.…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

OCT1-Mediated Metformin Uptake Regulates Pancreatic Stellate Cell Activity

Wu¹,

Qiu²,

Zhu³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Metformin treatment is reported to be associated with a lower incidence of and mortality from pancreatic cancer (PC) in type 2 diabetes patients. Activated pancreatic stellate cells (PSCs) are key stroma cells responsible for pancreatic fibrogenesis and PC progression. However, little research is about the influence of metformin on PSCs. Given the potential beneficial effects of metformin on PC, pancreatic tumour stroma is an important target for new therapeutics. We observed the effects of metformin on PSCs. We investigated the effects of metformin on human PSCs proliferation and the production of extracellular matrix (ECM) proteins. Methods: Cells were cultured with different concentrations of metformin (0-10 mmol/L). Cell proliferation was determined by immunofluorescence staining for nuclear Ki67 labelling. ECM production was studied by quantitative real-time polymerase chain reaction, immunoblotting and immunofluorescence microscopy. Adenosine monophosphate–activated protein kinase (AMPK), an important regulatory molecule responsible for metformin action, and the organic cation transporter member 1 (OCT1), which is believed to be the most important transporter for the pharmacological action of metformin, were investigated for their possible involvements in metformin-induced proliferation and ECM production. Results: Our results showed that metformin inhibited PSCs proliferation and decreased the production of ECM proteins by activation of AMPK phosphorylation. Silencing of OCT1 expression resulted in a reduction in the effects of metformin on PSCs activity. Conclusions: Collectively, the data indicate that OCT1 may contribute to uptake metformin and regulate PSCs activity. OCT1 is a target of metformin in regulating PSCs activity.

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The association between the expression of solute carrier transporters and the prognosis of pancreatic cancer

Abstract: This study identified a number of associations of transcript levels of SLCs with prognosis of pancreatic cancer patients.

Cited by 60 publications

References 41 publications

SLC transporters as a novel class of tumour suppressors: identity, function and molecular mechanisms

SLC transporters as a novel class of tumour suppressors: identity, function and molecular mechanisms

SLC22A3 polymorphisms do not modify pancreatic cancer risk, but may influence overall patient survival

OCT1-Mediated Metformin Uptake Regulates Pancreatic Stellate Cell Activity

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