Cancer Stem-like Properties in Colorectal Cancer Cells with Low Proteasome Activity

Munakata, Koji; Uemura, Mamoru; Tanaka, Shinji; Kawai, Kenji; Kitahara, Takeshi; Miyo, Masaaki; Kano, Yoshihiro; Nishikawa, Shinpei; Fukusumi, Takahito; Takahashi, Yusuke; Hata, Taishi; Nishimura, Junichi; Takemasa, Ichiro; Mizushima, Tsunekazu; Ikenaga, Masakazu; Kato, Takeshi; Murata, Kohei; Carethers, John M.; Yamamoto, Hirofumi; Doki, Yuichiro; Mori, Masaki

doi:10.1158/1078-0432.ccr-15-1945

Cited by 50 publications

(63 citation statements)

References 52 publications

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“…To further explore the underlying mechanism, we did the functional enrichment analysis of the candidate genes and genes which are highly correlated with these candidate genes. Our observed enrichment in the cell cycle is in line with previous studies, which suggested the cell cycle pathway is a determinant in the efficiency of CRC therapy [25,26]. The limitation of this study was the lack of the detailed information about the detail distance between tumor tissues and adjacent normal tissues.…”

Section: Discussionsupporting

confidence: 89%

Signature consist of nine differentially methylated gene pairs to predict the prognosis for stage II colorectal cancer patients

Zeng¹,

Li²,

Wei³

et al. 2018

Oncotarget

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Colorectal cancer (CRC) is the third most commonly malignance cancer worldwide. The quality of life and life expectancy of CRC survivors are seriously impacted by the recurrence after resection surgery. Therefore, there is a need to develop a reliable signature to predict the recurrence after resection surgery in CRC patients. Epigenetic alterations, especially gene methylation, have been found highly related to the metastasis of tumors. However, limited evidence is available for CRC patients. Moreover, there remains a knowledge gap of a comprehensive view of gene methylation in stage II CRC. In this study, we conducted and validated a differentially methylated 9-gene-pair prognosis signature to predict recurrence after resection surgery in stage II CRC patients. In addition, we use Univariable and Multivariable Cox regression to estimate the association between relapse free survival times in relation to each candidate gene pairs and the 9-gene-pair score. Moreover, the network analysis found 8 hub genes, including NDRG4 and BMP3, out of all candidate genes have large degree of interactions in the protein-protein interaction network. Seven hub genes have been found associated with CRC progression. Furthermore, the function enrichment analysis suggested that differentially methylated genes were mostly enriched in the cell cycle pathway. In summary, a 9-gene-pair signature was developed and validated in this study. The signatures identified in this study have the potential to be applied in the prognosis of post-surgery recurrence in the stage II CRC patents.

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Section: Discussionsupporting

confidence: 89%

Signature consist of nine differentially methylated gene pairs to predict the prognosis for stage II colorectal cancer patients

Zeng¹,

Li²,

Wei³

et al. 2018

Oncotarget

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“…Considering the very low fraction of LPACs that were found in the cancer cell lines (<1%), this suggests that LPACs might represent a subgroup of CSC-like cells, but clearly do not mark the whole CSC population. In line with this, in 2 of the 4 colon cancer cell lines used in this study, the LPAC population did not significantly demonstrate an enhanced sphere forming capacity (12). Previous studies on low proteasome CSCs also indicate that there is probably another CSC population that is not marked by low proteasome activity (69,73).…”

Section: Proteasome Activity As a Csc Markersupporting

confidence: 81%

“…In a recently published study, Munakata et al report on the relationship between treatment resistance, proteasome activity and CSC function in colorectal cancer (12). Similar to the above described studies, they made use of cell lines modified with a reporter for low proteasome activity.…”

Section: Proteasome Activity As a Csc Markermentioning

confidence: 99%

“…Interestingly, hypermethylation of the EID3 gene has been associated with colorectal neoplasia in African Americans, suggesting a tumor suppressing function for EID3 (78). In vitro modulation of this factor showed a positive correlation with proliferation and resistance to radio-and chemotherapy in colorectal cancer cells, but had no effect on proteasome activity (12). In addition, expression of EID3 mRNA could serve as a negative prognostic factor in CRC patients that underwent curative resection, suggesting that cells with high levels of EID3 are capable of reconstituting the original tumor and therefore could indeed function as cancer stem-like cells.…”

Section: Proteasome Activity As a Csc Markermentioning

confidence: 99%

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Cancer stem cells don’t waste their time cleaning—low proteasome activity, a marker for cancer stem cell function

Lenos¹,

Vermeulen²

2016

Ann. Transl. Med.

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A population of stem-like cells in tumors, the so-called cancer stem cells (CSCs), are being held responsible for therapy resistance and tumor recurrence. In analogy with normal stem cells, CSCs possess the capacity of long term self-renewal and multilineage differentiation. CSCs are believed to be more resistant to various therapies compared to their differentiated offspring and therefore the cause of tumor relapse. Markers for CSCs have been identified using xenograft transplantation assays and lineage tracing in mouse models, however the specificity and validity of many of these markers is under debate. Recently, low proteasome activity has been postulated as a novel CSC marker. In several solid malignancies a small subset of low proteasomal activity cells with CSC characteristics were identified, suggesting that proteasomal activity might be a functional marker for CSCs. In this perspective, we will discuss a recent study by Munakata et al., describing a population of colorectal cancer cells with CSC properties, characterized by low proteasome activity and treatment resistance. We will put this finding in a broader view by discussing the challenges and issues inherent with CSC identification, as well as some emerging insights in the CSC concept.

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“…Microarray analysis was performed as previously described (12,16,24). A total of 222 clinical samples were collected from consecutive patients who underwent curative (R0) resection for CRC from 2003 to 2006 at the Osaka University Hospital and its nine associated hospitals.…”

Section: Clinical Sample Collection and Microarray Analysismentioning

confidence: 99%

Fructose-bisphosphate aldolase A is a key regulator of hypoxic adaptation in colorectal cancer cells and involved in treatment resistance and poor prognosis

Kawai

Uemura

Munakata

et al. 2016

International Journal of Oncology

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Abstract.Hypoxia is an essential feature of cancer malignancy, but there are no methods for the routine detection of hypoxiainducible prognostic factors and potential therapeutic targets. We reported previously that the hypoxic tumor cells of metastatic liver tissue from patients with colorectal cancer (CRC) could be used as an 'in vivo' hypoxia culture model. Several potential hypoxia-inducible genes were identified using this model. Among them, one glycolytic enzyme was of special interest. There is currently increasing attention on glycolytic enzymes as potential therapeutic targets due to their association with cancer-specific metabolism. To better understand the molecular mechanisms of cancer malignancy, we investigated the expression of fructose-bisphosphate aldolase A (ALDOA) and its relationship with cancer metabolism. We found that ALDOA was induced by hypoxia in CRC-derived cell lines, and univariate and multivariate analyses of microarray data from the resected CRC samples of 222 patients revealed that ALDOA was an independent prognostic factor for CRC. We also analyzed the malignant potential of ALDOA in vitro using overexpression and knockdown assays. We found that ALDOA was negatively related to chemosensitivity and radiosensitivity and positively associated with proliferation, sphere formation and invasion in both normoxia and hypoxia. These associations were due to the roles of ALDOA in regulating glycolysis, the epithelial-mesenchymal transition and the cell cycle. These findings demonstrate that ALDOA is a hypoxiainducible prognostic factor that is closely related to CRC malignancy, and also provide new insights into the importance of ALDOA and glycolysis in cancer and suggest new targets for anticancer therapies.

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Cancer Stem-like Properties in Colorectal Cancer Cells with Low Proteasome Activity

Abstract: LPACs have characteristic treatment resistance and act as CSCs in colorectal cancer. In addition, EID3 is one of the potential regulators of treatment resistance in colorectal cancer and may be a potential therapeutic target. Clin Cancer Res; 22(21); 5277-86. ©2016 AACR.

Cited by 50 publications

References 52 publications

Signature consist of nine differentially methylated gene pairs to predict the prognosis for stage II colorectal cancer patients

Signature consist of nine differentially methylated gene pairs to predict the prognosis for stage II colorectal cancer patients

Cancer stem cells don’t waste their time cleaning—low proteasome activity, a marker for cancer stem cell function

Fructose-bisphosphate aldolase A is a key regulator of hypoxic adaptation in colorectal cancer cells and involved in treatment resistance and poor prognosis

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