Dataset Information

HMGA2 enhances 5-fluorouracil chemoresistance in colorectal cancer via the Dvl2/Wnt pathway.

ABSTRACT: Drug resistance is one of the main hurdles to overcome for the improvement of cancer patient survival. However, the underlying mechanisms remain largely unknown, and therapeutic options are limited. Here, we demonstrate a strong correlation between HMGA2 expression and chemosensitivity to 5-fluorouracil (5-FU), a widely used first-line systemic chemotherapy regimen for colorectal cancer (CRC) patients. Overexpression of HMGA2 enhances chemoresistance to 5-FU of CRC both in vitro and in vivo. Further experiments indicate that HMGA2 directly binds to the promoter of Dvl2 and induces its transcription, which leads to increased activation of the Wnt/?-catenin pathway. Taken together, our data suggest that HMGA2 enhances the chemoresistance to 5-FU in CRC via activating the Dvl2/Wnt pathway. Therefore, HMGA2 may serve as a predictive biomarker and a potential therapeutic target in CRC.

SUBMITTER: Xu X

PROVIDER: S-EPMC5839414 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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HMGA2 enhances 5-fluorouracil chemoresistance in colorectal cancer via the Dvl2/Wnt pathway.

Xu Xi X Wang Yunfeng Y Deng Hong H Liu Chungang C Wu Jingjing J Lai Maode M

Oncotarget 20180110 11

Drug resistance is one of the main hurdles to overcome for the improvement of cancer patient survival. However, the underlying mechanisms remain largely unknown, and therapeutic options are limited. Here, we demonstrate a strong correlation between HMGA2 expression and chemosensitivity to 5-fluorouracil (5-FU), a widely used first-line systemic chemotherapy regimen for colorectal cancer (CRC) patients. Overexpression of HMGA2 enhances chemoresistance to 5-FU of CRC both <i>in vitro</i> and <i>in ...[more]

PMID: 29515783

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Project description:Sanguisorba officinalis L., a traditional Chinese medicine (TCM) called DiYu (DY) in China, has a strong tradition of utilization as a scorching, blood-cooling, and hemostatic medication, and was used for cancer prevention and treatment due to its potential immune-enhancing and hematological toxicity-reducing effects. Previous studies have reported significant effects of DY on cancers including colorectal cancer (CRC), which is one of the most common malignancies worldwide. The first-line cure 5-fluorouracil (5-FU) plays decisive commerce in the sedative of CRC as a clinically available chemotherapeutic agent. One of the primary causes of cancer treatment failure is the acquisition of chemotherapy drug resistance. In order to successfully combat the emergence of chemoresistance, it is essential to identify herbs or traditional Chinese medicine that have adjuvant therapeutic effects on CRC. Therefore, this study aimed to determine whether DY could improve the sensitivity, conquer the chemoresistance of 5-FU-resistant CRC cells, and investigate its intrinsic mechanism.Materials and methodsMTT, Hoechst 33258 staining, and flow cytometry assays were used to determine the anticancer activity of DY alone or in combination with 5-FU against 5-FU-resistant CRC cells (RKO-R and HCT15-R) and wound healing assays were conducted to detect cell migration. Transcriptomic techniques were carried out to explore the effect and mechanism of DY on drug-resistant CRC cells. Western Blot and RT q-PCR assays were performed to validate the mechanism by which DY overcomes drug-resistant CRC cells.ResultsThese results indicated that DY alone or in combination with 5-FU significantly inhibited the proliferation and the migration of resistant CRC cells, and potentiated the susceptibility of 5-FU to drug-resistant CRC cells. GO and KEGG enrichment analysis showed that the mechanisms of drug resistance in CRC cells and DY against drug-resistant CRC cells highly overlapped, involved in the modulation of biological processes such as cell migration, positive regulation of protein binding and cytoskeleton, and MAPK (Ras-ERK-MEK), PI3K/Akt, and other signaling pathways. Moreover, DY can mediate the expression of p-R-Ras, p-ERK1/2, p-MEK1/2, p-PI3K, p-AKT, HIF-1A and VEGFA proteins. In addition, DY significantly suppressed the expression of AKT3, NEDD9, BMI-1, and CXCL1 genes in resistant CRC cells.ConclusionIn conclusion, DY could inhibit the proliferation and migration of 5-FU-resistant cells and strengthen the sensitivity of 5-FU to CRC-resistant cells. Furthermore, DY may prevail over chemoresistance through the Ras/MEK/ERK and PI3K/Akt pathways. These findings imply that DY may be a potential drug for clinical treatment or adjuvant treatment of drug-resistant CRC.

Project description:Simple Summary 5-fluorouracil (5-FU) has been the treatment of choice against colorectal cancer (CRC) for the past six decades. However, 5-FU exhibits high toxicity and drug resistance in CRC patients, highlighting the need for less toxic and more efficient treatments. The pentose phosphate pathway (PPP) is upregulated in cancer cells and promotes their survival. Recently, mannose has been reported to halt tumor growth and impair the PPP. We studied the effect of mannose, alone and in combination with 5-FU in human CRC cells and animal models. We have shown that mannose alone or in combination with 5-FU downregulated the PPP and enhanced the sensitivity of CRC cancer cells and tumors in mice to 5-FU. Therefore, this research may pave the way for better patient care. Abstract Colorectal cancer (CRC) is one of the leading cancers and causes of death in patients. 5-fluorouracil (5-FU) is the therapy of choice for CRC, but it exhibits high toxicity and drug resistance. Tumorigenesis is characterized by a deregulated metabolism, which promotes cancer cell growth and survival. The pentose phosphate pathway (PPP) is required for the synthesis of ribonucleotides and the regulation of reactive oxygen species and is upregulated in CRC. Mannose was recently reported to halt tumor growth and impair the PPP. Mannose inhibitory effects on tumor growth are inversely related to the levels of phosphomannose isomerase (PMI). An in silico analysis showed low PMI levels in human CRC tissues. We, therefore, investigated the effect of mannose alone or in combination with 5-FU in human CRC cell lines with different p53 and 5-FU resistance statuses. Mannose resulted in a dose-dependent inhibition of cell growth and synergized with 5-FU treatment in all tested cancer cell lines. Mannose alone or in combination with 5-FU reduced the total dehydrogenase activity of key PPP enzymes, enhanced oxidative stress, and induced DNA damage in CRC cells. Importantly, single mannose or combination treatments with 5-FU were well tolerated and reduced tumor volumes in a mouse xenograft model. In summary, mannose alone or in combination with 5-FU may represent a novel therapeutic strategy in CRC.

Dataset Information

HMGA2 enhances 5-fluorouracil chemoresistance in colorectal cancer via the Dvl2/Wnt pathway.

Publications

HMGA2 enhances 5-fluorouracil chemoresistance in colorectal cancer via the Dvl2/Wnt pathway.

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