The Sixth Peoples Hospital of Jinan City

Jinan, China

The Sixth Peoples Hospital of Jinan City

Jinan, China
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Zhao X.-Q.,Shandong University | Zhang Y.-F.,Yantai University | Xia Y.-F.,The Sixth Peoples Hospital of Jinan City | Zhou Z.-M.,Taian Central Hospital | Cao Y.-Q.,Taian Central Hospital
Oncology Letters | Year: 2015

The mechanisms underlying drug resistance in colorectal cancer (CRC) treatment remain to be fully elucidated. Therefore, the present study aimed to investigate the underlying mechanism resistance to a widely used anticancer drug, 5‑Fluorouracil (5‑FU). Nuclear factor‑erythroid 2‑related factor 2 (Nrf2) is an important transcription factor involved in cellular protection. In the present study, it was hypothesized that the epigenetic modification of Nrf2 may be a potential target for 5‑FU resistance in CRC treatment. Protein and messenger RNA levels of Nrf2, heme oxygenase‑1 (HO‑1), DNA methylases and DNA methyltransferases were determined and DNA methylation analysis for the Nrf2 promoter was performed in a human CRC control (SNU‑C5) and resistant (SNU‑C5R) cell line. The results demonstrated that Nrf2 expression levels, nuclear translocation and promoter binding were significantly increased in SNU‑C5R cells compared with SNU‑C5 cells. Elevated levels of activated Nrf2 in SNU‑C5R cells resulted in the increased protein expression and activity of HO‑1. In addition, increased production of reactive oxygen species (ROS) and upregulation of ten‑eleven translocation (TET)1 were observed in SNU‑C5R cells compared with SNU‑C5 cells. Furthermore, methylation analysis revealed Nrf2 promoter cytosine‑phosphate‑guanine island hypomethylation in 5‑FU‑treated cells. In conclusion, the results indicated that 5‑FU‑induced ROS production resulted in the upregulation of TET1 expression and function. In addition, these results indicated that TET‑dependent demethylation of the Nrf2 promoter upregulated Nrf2 and HO‑1 expression, which induced cellular protection mechanisms, ultimately leading to drug resistance. © 2015, Spandidos Publications. All rights reserved.


PubMed | The Sixth Peoples Hospital of Jinan City, Taian Central Hospital, Yantai University and Shandong University
Type: Journal Article | Journal: Oncology letters | Year: 2015

The mechanisms underlying drug resistance in colorectal cancer (CRC) treatment remain to be fully elucidated. Therefore, the present study aimed to investigate the underlying mechanism resistance to a widely used anticancer drug, 5-Fluorouracil (5-FU). Nuclear factor-erythroid 2-related factor 2 (Nrf2) is an important transcription factor involved in cellular protection. In the present study, it was hypothesized that the epigenetic modification of Nrf2 may be a potential target for 5-FU resistance in CRC treatment. Protein and messenger RNA levels of Nrf2, heme oxygenase-1 (HO-1), DNA methylases and DNA methyltransferases were determined and DNA methylation analysis for the Nrf2 promoter was performed in a human CRC control (SNU-C5) and resistant (SNU-C5R) cell line. The results demonstrated that Nrf2 expression levels, nuclear translocation and promoter binding were significantly increased in SNU-C5R cells compared with SNU-C5 cells. Elevated levels of activated Nrf2 in SNU-C5R cells resulted in the increased protein expression and activity of HO-1. In addition, increased production of reactive oxygen species (ROS) and upregulation of ten-eleven translocation (TET)1 were observed in SNU-C5R cells compared with SNU-C5 cells. Furthermore, methylation analysis revealed Nrf2 promoter cytosine-phosphate-guanine island hypomethylation in 5-FU-treated cells. In conclusion, the results indicated that 5-FU-induced ROS production resulted in the upregulation of TET1 expression and function. In addition, these results indicated that TET-dependent demethylation of the Nrf2 promoter upregulated Nrf2 and HO-1 expression, which induced cellular protection mechanisms, ultimately leading to drug resistance.


Wang F.,Shandong University | Ma Z.B.,Shandong University | Fu Q.Y.,Shandong University | Fang Y.Z.,The Sixth Peoples Hospital of Jinan City | And 6 more authors.
Chinese Medical Journal | Year: 2014

Background Breast cancer has become one of the most common malignant tumors among females over the past several years. Breast carcinogenesis is a continuous process, which is featured by the normal epithelium progressing to premalignant lesions and then to invasive breast cancer (IBC). Targeting premalignant lesions is an effective strategy to prevent breast cancer. The establishment of animal models is critical to study the mechanisms of breast carcinogenesis, which will facilitate research on breast cancer prevention and drug behaviors. In this study, we established a feasible chemically-induced rat model of premalignant breast cancer. Methods Following the administration of the drugs (carcinogen, estrogen, and progestogen) to Sprague-Dawley (SD) rats, tumors or suspicious tumors were identified by palpation or ultrasound imaging, and were surgically excised for pathological evaluation. A series of four consecutive steps were carried out in order to determine the carcinogen: 7,12-dimethylbenzaanthracene (DMBA) or 1-methyl-1-nitrosourea, the route of carcinogen administration, the administration period of estrogen and progestogen, and the DMBA dosage. Results Stable premalignant lesions can be induced in SD rats on administration of DMBA (15 mg/kg, administered three times) followed by administration of female hormones 5-day cycle. Results were confrmed by ultrasound and palpation. Conclusion Under the premise of drug dose and cycle, DMBA combined with estrogen and progestogen can be used as a SD rat model for breast premalignant lesions.

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