Aberrant epigenetic patterns in the etiology of gastrointestinal cancers

Karpiński, Paweł; Sąsiadek, Maria M.; Blin, Nikolaus

doi:10.1007/bf03195243

Cited by 27 publications

(24 citation statements)

References 78 publications

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“…Colorectal cancer (CRC) is still the third most common cancer and the second most common cause of cancer-related death worldwide, although considerable progress has been made in the treatment of CRC in recent years12. Thus far, 5-fluorouracil (5-FU) remains a widely used chemotherapeutic drug in the treatment of various cancers, including colorectal carcinoma, breast cancer, gastric cancer and other solid tumors.…”

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confidence: 99%

RETRACTED ARTICLE: JNK confers 5-fluorouracil resistance in p53-deficient and mutant p53-expressing colon cancer cells by inducing survival autophagy

Sui

Kong

Wang

et al. 2014

Sci Rep

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Deficiency or mutation in the p53 tumor suppressor gene commonly occurs in human cancer and can contribute to disease progression and chemotherapy resistance. Currently, although the pro-survival or pro-death effect of autophagy remains a controversial issue, increasing data seem to support the idea that autophagy facilitates cancer cell resistance to chemotherapy treatment. Here we report that 5-FU treatment causes aberrant autophagosome accumulation in HCT116 p53−/− and HT-29 cancer cells. Specific inhibition of autophagy by 3-MA, CQ or small interfering RNA treatment targeting Atg5 or Beclin 1 can potentiate the re-sensitization of these resistant cancer cells to 5-FU. In further analysis, we show that JNK activation and phosphorylation of Bcl-2 are key determinants in 5-FU-induced autophagy. Inhibition of JNK by the compound SP600125 or JNK siRNA suppressed autophagy and phosphorylation of c-Jun and Bcl-2 but increased 5-FU-induced apoptosis in both HCT116 p53−/− and HT29 cells. Taken together, our results suggest that JNK activation confers 5-FU resistance in HCT116 p53−/− and HT29 cells by promoting autophagy as a pro-survival effect, likely via inducing Bcl-2 phosphorylation. These results provide a promising strategy to improve the efficacy of 5-FU-based chemotherapy for colorectal cancer patients harboring a p53 gene mutation.

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confidence: 99%

RETRACTED ARTICLE: JNK confers 5-fluorouracil resistance in p53-deficient and mutant p53-expressing colon cancer cells by inducing survival autophagy

Sui

Kong

Wang

et al. 2014

Sci Rep

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“…Colorectal cancer (CRC) is still a leading cause of cancer-related morbidity and mortality around the world, although a lot of progress has been made in the treatment of CRC over the past years [1], [2]. Epidemiologic studies have shown that diabetes mellitus (DM) increases incidence and mortality of cancers, especially gastrointestinal malignancy [3], [4].…”

Section: Introductionmentioning

confidence: 99%

Use of Metformin Alone Is Not Associated with Survival Outcomes of Colorectal Cancer Cell but AMPK Activator AICAR Sensitizes Anticancer Effect of 5-Fluorouracil through AMPK Activation

Sui

Yang

et al. 2014

PLoS ONE

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Colorectal cancer (CRC) is still the third most common cancer and the second most common causes of cancer-related death around the world. Metformin, a biguanide, which is widely used for treating diabetes mellitus, has recently been shown to have a suppressive effect on CRC risk and mortality, but not all laboratory studies suggest that metformin has antineoplastic activity. Here, we investigated the effect of metformin and AMPK activator AICAR on CRC cells proliferation. As a result, metformin did not inhibit cell proliferation or induce apoptosis for CRC cell lines in vitro and in vivo. Different from metformin, AICAR emerged antitumor activity and sensitized anticancer effect of 5-FU on CRC cells in vitro and in vivo. In further analysis, we show that AMPK activation may be a key molecular mechanism for the additive effect of AICAR. Taken together, our results suggest that metformin has not antineoplastic activity for CRC cells as a single agent but AMPK activator AICAR can induce apoptosis and enhance the cytotoxic effect of 5-FU through AMPK activation.

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“…This might indicate the importance of APC inactivation in tumorigenesis of these organs [31]. Moreover, recent reports indicate that APC is an important prognostic indicator for unfavorable clinicopathological outcome and tumor recurrence in several types of cancers [29,30].…”

Section: Introductionmentioning

confidence: 99%

Qualitative analysis of Adenomatous Polyposis Coli promoter: Hypermethylation, engagement and effects on survival of patients with esophageal cancer in a high risk region of the world, a potential molecular marker

et al. 2009

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BackgroundSquamous cell carcinoma of esophagus (SCCE) occurs at a high incidence rate in certain parts of the world. This feature necessitates that different aspects of the disease and in particular genetic characteristics be investigated in such regions. In addition, such investigations might lead to achievement of molecular markers helpful for early detection, successful treatment and follow up of the disease. Adenomatous Polyposis Coli (APC) promoter hypermethylation has been shown to be a suitable marker for both serum and solid tumors of adenocarcinoma of esophagus. We investigated the status of APC promoter hypermethylation in Iranian patients, compared the results with the former studies, and evaluated its applicability as a candidate molecular marker by examining association between survival of SCCE patients and APC promoter methylation.MethodsFor evaluating the status of APC promoter hypermethylation and its association with SCCE, a qualitative methylation specific PCR (MSP) was used. DNA was extracted and digested with an appropriate restriction enzyme, treated with sodium bisulfite in agarose beads and amplified in two-step PCR reaction by applying either methylated or unmethylated promoter specific primers. Universally methylated DNA and methylase treated blood DNA of healthy donors were used as positive controls as well. Survival of patients was followed up for two years after treatment and survival rate of patients with methylated APC promoter was compared with that of unmethylated patients.ResultsAssessment of APC promoter methylation revealed that normal tissues were unmethylated, while twenty out of forty five (44.4%) tumor tissues were hypermethylated either in one or both alleles of APC. Among the tissues in which methylation was detected, seven were hypermethylated in both alleles while the other thirteen were hypermethylated in one of the two alleles of APC. Analyzing two-year survival rate of patients with respect to promoter hypermethylation showed a lower rate of survival for patients with methylated APC promoter following their treatment. Further investigation into the association between promoter hypermethylation and tumor differentiation status indicated that patients with well differentiated tumors were more likely to develop promoter hypermethylation.ConclusionObserving similar level of APC promoter hypermethylation in patients with SCCE in this high risk region and comparing it with other parts of the world could support the hypothesis that a common molecular mechanism might be involved in tumorigenesis of SCCE. In addition, the higher rate of two-year survival for patients with unmethylated APC promoter as well as its relationship with tumor differentiation would suggest that this tumor suppressor could be an appropriate candidate molecular marker for evaluating tumor malignancy and predicting survival of patients subsequent to treatment.

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Aberrant epigenetic patterns in the etiology of gastrointestinal cancers

Cited by 27 publications

References 78 publications

RETRACTED ARTICLE: JNK confers 5-fluorouracil resistance in p53-deficient and mutant p53-expressing colon cancer cells by inducing survival autophagy

RETRACTED ARTICLE: JNK confers 5-fluorouracil resistance in p53-deficient and mutant p53-expressing colon cancer cells by inducing survival autophagy

Use of Metformin Alone Is Not Associated with Survival Outcomes of Colorectal Cancer Cell but AMPK Activator AICAR Sensitizes Anticancer Effect of 5-Fluorouracil through AMPK Activation

Qualitative analysis of Adenomatous Polyposis Coli promoter: Hypermethylation, engagement and effects on survival of patients with esophageal cancer in a high risk region of the world, a potential molecular marker

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