Long-Term Cisplatin Exposure Promotes Methylation of the OCT1 Gene in Human Esophageal Cancer Cells

Lin, Rui; Li, Xiaoli; Li, Jiansheng; Zhang, Lianfeng; Xu, Feng; Chu, Yanqi; Li, Jichang

doi:10.1007/s10620-012-2424-9

Cited by 26 publications

(15 citation statements)

References 21 publications

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“…In the case of HCC, this event may be at least partially due to an enhanced methylation and reduced activity of the SLC22A1 promoter . OCT1 down‐regulation has already been associated with chemoresistance in certain types of cancer, for instance, to cisplatin . Moreover, OCT1 expression levels have been suggested to be a useful biomarker to predict the success of imatinib‐based therapy for chronic myeloid leukemia .…”

Section: Discussionmentioning

confidence: 99%

“…30 OCT1 down-regulation has already been associated with chemoresistance in certain types of cancer, for instance, to cisplatin. 31 Moreover, OCT1 expression levels have been suggested to be a useful biomarker to predict the success of imatinib-based therapy for chronic myeloid leukemia. 32 The present study suggests that reduced OCT1-mediated sorafenib uptake may be involved in a poorer response to this drug.…”

Section: Discussionmentioning

confidence: 99%

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Expression of Slc22a1 Variants May Affect the Response of Hepatocellular Carcinoma And Cholangiocarcinoma To Sorafenib

et al. 2013

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Reduced drug uptake is an important mechanism of chemoresistance. Down-regulation of SLC22A1 encoding the organic cation transporter-1 (OCT1) may affect the response of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CGC) to sorafenib, a cationic drug. Here we investigated whether SLC22A1 variants may contribute to sorafenib chemoresistance. Complete sequencing and selective variant identification were carried out to detect single nucleotide polymorphisms (SNPs) in SLC22A1 complementary DNA (cDNA). In HCC and CGC biopsies, in addition to previously described variants, two novel alternative spliced variants and three SNPs were identified. To study their functional consequences, these variants were mimicked by directed mutagenesis and expressed in HCC (Alexander and SK-Hep-1) and CGC (TFK1) cells. The two novel described variants, R61S fs*10 and C88A fs*16, encoded truncated proteins unable to reach the plasma membrane. Both variants abolished OCT1-mediated uptake of tetraethylammonium, a typical OCT1 substrate, and were not able to induce sorafenib sensitivity. In cells expressing functional OCT1 variants, OCT1 inhibition with quinine prevented sorafenib-induced toxicity. Expression of OCT1 variants in Xenopus laevis oocytes and determination of quinine-sensitive sorafenib uptake by high-performance liquid chromatography-dual mass spectrometry confirmed that OCT1 is able to transport sorafenib and that R61S fs*10 and C88A fs*16 abolish this ability. Screening of these SNPs in 23 HCC and 15 CGC biopsies revealed that R61S fs*10 was present in both HCC (17%) and CGC (13%), whereas C88A fs*16 was only found in HCC (17%). Considering all SLC22A1 variants, at least one inactivating SNP was found in 48% HCC and 40% CGC. Conclusion: Development of HCC and CGC is accompanied by the appearance of aberrant OCT1 variants that, together with decreased OCT1 expression, may dramatically affect the ability of sorafenib to reach active intracellular concentrations in these tumors. (HEPATOLOGY 2013;58:1065-1073 H epatocellular carcinoma (HCC) and cholangiocarcinoma (CGC) are important causes of cancer-related death worldwide. Although surgery is potentially curative for patients with localized disease, these tumors are often in an advanced stage at the time of diagnosis, when surgery is no longer the

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Expression of Slc22a1 Variants May Affect the Response of Hepatocellular Carcinoma And Cholangiocarcinoma To Sorafenib

et al. 2013

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“…Moreover, OCT1 is linked to various human tumors. The abnormal expression of OCT1 is associated with a poor patient survival rate and tumor progression [5][6][7]. However, little is known about the roles of OCT1 in colorectal carcinogenesis.…”

Section: Introductionmentioning

confidence: 99%

Octamer transcription factor 1 mediates epithelial-mesenchymal transition in colorectal cancer

et al. 2015

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Colorectal cancer (CRC) is one of the most common cancer types worldwide. Octamer transcription factor 1 (OCT1) is associated with tumor progression and a poor patient survival rate. However, little is known regarding the effect of OCT1 in CRC. Moreover, because the epithelial-to-mesenchymal transition (EMT) is a key player in metastasis, whether OCT1 induces EMT in CRC remains unclear. In the present study, we investigate the role of OCT1 in CRC and its expression pattern and clinical significance. The expression of OCT1 in CRC tissues and the adjacent noncancerous tissues was detected using quantitative real-time PCR (QRT-PCR), Western blot, and immunohistochemistry analyses. In addition, silencing of OCT1 with small interfering RNA (siRNA) was performed in CRC cell lines, and the impact on proliferation, migration, and the EMT marker of CRC was analyzed. Our results found that OCT1 levels were significant higher in CRC tissues compared with the adjacent noncancerous tissues. Furthermore, OCT1 siRNA significantly reduced the proliferation rate of SW620 and LoVo cells, inhibited the migration and invasion, and could reverse EMT in these two CRC cells, indicating that OCT1 plays a critical role in CRC progression.

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“…OCT1 promotes the tumor engraftment frequency and the potential of hematopoietic stem cell engraftment in competitive and serial transplants (7). An additional study revealed that methylation of the OCT1 gene in human esophageal cancer cells is induced by long-term cisplatin exposure, resulting in cisplatin resistance (8). The abnormal change of OCT1 is associated with tumor progression and a poor patient survival rate (9).…”

Section: Introductionmentioning

confidence: 99%

High expression of octamer transcription factor 1 in cervical cancer

et al. 2014

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Abstract. Cervical carcinoma is the second most prevalent malignancy in females worldwide. The crucial etiologic factors involved in the development of cervical carcinoma include infection with papillomavirus, and the structural or functional mutation of oncogenes and tumor suppressor genes. The abnormal change of octamer transcription factor 1 (OCT1) is associated with tumor progression and a poor patient survival rate. However, little is known regarding the effect of OCT1 in cervical cancer. In the present study, flow cytometry, western blot analysis and quantitative polymerase chain reaction (qPCR) were peformed to identify differentially expressed OCT1 in cervical cancer tissue and adjacent non-cancerous tissues. The normalized OCT1 gene expression in cervical cancer was 5.98 times higher compared with the adjacent non-cancerous tissues. Western blot analysis and flow cytometry assessed the levels of OCT1 protein.The results of these two differential techniques showed that the protein expression level of OCT1 was greater in cervical cancer tissues, which corresponded with the qPCR results. Finally, as OCT1 is a potential target gene for microRNA (miR)-1467, -1185, -4493 and -3919, their expression levels were analyzed in cervical cancer tissues and adjacent non-cancerous tissues; they were downregulated by ~45% in the cervical cancer samples. The results of the present study showed that OCT1 is highly expressed in cervical cancer tissues and indicated that OCT-1 may be significant in cervical cancer.

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Long-Term Cisplatin Exposure Promotes Methylation of the OCT1 Gene in Human Esophageal Cancer Cells

Abstract: This study shows that long-term exposure to cisplatin promotes methylation of the OCT1 gene in human esophageal cancer cells, which in turn results in cisplatin resistance.

Cited by 26 publications

References 21 publications

Expression of Slc22a1 Variants May Affect the Response of Hepatocellular Carcinoma And Cholangiocarcinoma To Sorafenib

Expression of Slc22a1 Variants May Affect the Response of Hepatocellular Carcinoma And Cholangiocarcinoma To Sorafenib

Octamer transcription factor 1 mediates epithelial-mesenchymal transition in colorectal cancer

High expression of octamer transcription factor 1 in cervical cancer

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