RNAi mediated silencing of Nanog expression suppresses the growth of human colorectal cancer stem cells

Abstract Background: Colorectal cancer (CRC) is the third most common cancer in the world known for its poor recurrence-free prognosis. Previous studies have shown that it is closely linked with cancer stem cells (CSCs), which have self-renewal potential and the capacity to differentiate into diverse populations. Nanog is an important transcription factor that functions to maintain the self-renewal and proliferation of embryonic stem cells; however, many recent studies have shown that Nanog is also highly expressed in many cancer stem cells.Methods: To investigate whether Nanog plays a crucial role in maintaining the stemness of colorectal CSCs (CCSCs), RNA interference was used to downregulate Nanog expression in the CRC stem cell line, EpCAM+CD44+HCT-116. We examined the anti-tumor function of Nanog in vitro and in vivo, using small interfering RNA.Results: Our results revealed that the Nanog mRNA expression level in CCSCs was higher than that in HCT-116 cells. We found that the depletion of Nanog inhibited proliferation and promoted apoptosis in EpCAM+CD44+HCT-116 cells. In addition, the invasive ability of EpCAM+CD44+HCT-116 cells was markedly restricted when Nanog was silenced by small interfering RNA. Furthermore, we found that the silencing of Nanog decreased tumor size and weight and improved the survival rate of tumor-bearing mice.Conclusions: In conclusion, these findings collectively demonstrate that Nanog, which is highly expressed in CRC stem cells, is a key factor in the development of tumor growth, and it may serve as a potential marker of prognosis and a novel and effective therapeutic target for the treatment of CRC.

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RNAi mediated silencing of Nanog expression suppresses the growth of human colorectal cancer stem cells

10.21203/rs.3.rs-22167/v2 ◽

2020 ◽

Author(s):

Chen Zhang ◽

Yuanyuan Zhao ◽

Yongjing Yang ◽

Chunlian Zhong ◽

Tianju Ji ◽

...

Keyword(s):

Colorectal Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Small Interfering Rna ◽

Embryonic Stem ◽

Self Renewal ◽

Nanog Expression ◽

Hct 116 ◽

Hct 116 Cells ◽

Interfering Rna

Abstract Background: Colorectal cancer (CRC) is the third most common cancer in the world known for its poor recurrence-free prognosis. Previous studies have shown that it is closely linked with cancer stem cells (CSCs), which have self-renewal potential and the capacity to differentiate into diverse populations. Nanog is an important transcription factor that functions to maintain the self-renewal and proliferation of embryonic stem cells; however, many recent studies have shown that Nanog is also highly expressed in many cancer stem cells. Methods: To investigate whether Nanog plays a crucial role in maintaining the stemness of colorectal CSCs (CCSCs), RNA interference was used to downregulate Nanog expression in the CRC stem cell line, EpCAM + CD44 + HCT-116. We examined the anti-tumor function of Nanog in vitro and in vivo, using small interfering RNA. Results: Our results revealed that the Nanog mRNA expression level in CCSCs was higher than that in HCT-116 cells. We found that the depletion of Nanog inhibited proliferation and promoted apoptosis in EpCAM + CD44 + HCT-116 cells. In addition, the invasive ability of EpCAM + CD44 + HCT-116 cells was markedly restricted when Nanog was silenced by small interfering RNA. Furthermore, we found that the silencing of Nanog decreased tumor size and weight and improved the survival rate of tumor-bearing mice. Conclusions: In conclusion, these findings collectively demonstrate that Nanog, which is highly expressed in CRC stem cells, is a key factor in the development of tumor growth, and it may serve as a potential marker of prognosis and a novel and effective therapeutic target for the treatment of CRC.

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G9a controls pluripotent-like identity and tumor-initiating function in human colorectal cancer

Oncogene ◽

10.1038/s41388-020-01591-7 ◽

2020 ◽

Author(s):

Christopher J. Bergin ◽

Aïcha Zouggar ◽

Joshua R. Haebe ◽

Angelique N. Masibag ◽

François M. Desrochers ◽

...

Keyword(s):

Colorectal Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Embryonic Stem ◽

Transcriptome Profiling ◽

Histone Methyltransferase ◽

Cell Phenotype ◽

Regulation Mechanism ◽

Self Renewal ◽

Undifferentiated State

AbstractColorectal tumors are hierarchically organized and governed by populations of self-renewing cancer stem cells, representing one of the deadliest types of cancers worldwide. Emergence of cancer stemness phenotype depends on epigenetic reprogramming, associated with profound transcriptional changes. As described for pluripotent reprogramming, epigenetic modifiers play a key role in cancer stem cells by establishing embryonic stem-like transcriptional programs, thus impacting the balance between self-renewal and differentiation. We identified overexpression of histone methyltransferase G9a as a risk factor for colorectal cancer, associated with shorter relapse-free survival. Moreover, using human transformed pluripotent cells as a surrogate model for cancer stem cells, we observed that G9a activity is essential for the maintenance of embryonic-like transcriptional signature promoting self-renewal, tumorigenicity, and undifferentiated state. Such a role was also applicable to colorectal cancer, where inhibitors of G9a histone methyltransferase function induced intestinal differentiation while restricting tumor-initiating activity in patient-derived colorectal tumor samples. Finally, by integrating transcriptome profiling with G9a/H3K9me2 loci co-occupancy, we identified the canonical Wnt pathway, epithelial-to-mesenchyme transition, and extracellular matrix organization as potential targets of such a chromatin regulation mechanism in colorectal cancer stem cells. Overall, our findings provide novel insights on the role of G9a as a driver of cancer stem cell phenotype, promoting self-renewal, tumorigenicity, and undifferentiated state.

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Erratum: Corrigendum: Adenylate kinase hCINAP determines self-renewal of colorectal cancer stem cells by facilitating LDHA phosphorylation

Nature Communications ◽

10.1038/ncomms16000 ◽

2017 ◽

Vol 8 (1) ◽

Author(s):

Yapeng Ji ◽

Chuanzhen Yang ◽

Zefang Tang ◽

Yongfeng Yang ◽

Yonglu Tian ◽

...

Keyword(s):

Colorectal Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Adenylate Kinase ◽

Self Renewal ◽

Colorectal Cancer Stem Cells

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The FDA-Approved Anti-Asthma Medicine Ciclesonide Inhibits Lung Cancer Stem Cells through Hedgehog Signaling-Mediated SOX2 Regulation

International Journal of Molecular Sciences ◽

10.3390/ijms21031014 ◽

2020 ◽

Vol 21 (3) ◽

pp. 1014 ◽

Cited By ~ 5

Author(s):

Hack Sun Choi ◽

Su-Lim Kim ◽

Ji-Hyang Kim ◽

Dong-Sun Lee

Keyword(s):

Lung Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Small Interfering Rna ◽

Hedgehog Signaling ◽

Underlying Mechanism ◽

Inhibitory Effect ◽

Protein Levels ◽

Lung Cancer Stem Cells ◽

Interfering Rna

Ciclesonide is an FDA-approved glucocorticoid (GC) used to treat asthma and allergic rhinitis. However, its effects on cancer and cancer stem cells (CSCs) are unknown. Our study focuses on investigating the inhibitory effect of ciclesonide on lung cancer and CSCs and its underlying mechanism. In this study, we showed that ciclesonide inhibits the proliferation of lung cancer cells and the growth of CSCs. Similar glucocorticoids, such as dexamethasone and prednisone, do not inhibit CSC formation. We show that ciclesonide is important for CSC formation through the Hedgehog signaling pathway. Ciclesonide reduces the protein levels of GL1, GL2, and Smoothened (SMO), and a small interfering RNA (siRNA) targeting SMO inhibits tumorsphere formation. Additionally, ciclesonide reduces the transcript and protein levels of SOX2, and an siRNA targeting SOX2 inhibits tumorsphere formation. To regulate breast CSC formation, ciclesonide regulates GL1, GL2, SMO, and SOX2. Our results unveil a novel mechanism involving Hedgehog signaling and SOX2 regulated by ciclesonide in lung CSCs, and also open up the possibility of targeting Hedgehog signaling and SOX2 to prevent lung CSC formation.

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