Subcellular localisation of the stem cell markers OCT4, SOX2, NANOG, KLF4 and c-MYC in cancer: a review

Schaijik, Bede van; Davis, Paul F.; Wickremesekera, Agadha; Tan, Swee T.; Itinteang, Tinte

doi:10.1136/jclinpath-2017-204815

Cited by 161 publications

(120 citation statements)

References 52 publications

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“…It was reported that the stem cell associated genes, including OCT4, SOX-2 and Nanog and so on, have important roles in liver CSCs regulation. [25][26][27] As expected, miR-365 overexpression downregulated the expression of stemness-associated genes ( Figures 3A and 3B) and liver CSC markers in hepatoma cells ( Figures 3C and 3D), which further supported that miR-365 could inhibit liver CSCs expansion.…”

Section: Mir-365 Suppressed Liver Cscs Expansionsupporting

confidence: 82%

miR‐365 regulates liver cancer stem cells via RAC1 pathway

Jiang

Liu

et al. 2018

Molecular Carcinogenesis

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Liver cancer stem cells (CSCs) were involved in tumorigenesis, progression, recurrence, and drug resistance of hepatocellular carcinoma (HCC). miR-365 was downregulated in hepatocellular carcinoma and inhibited HCC cell proliferation and invasion. However, the role of miR-365 in liver cancer stem cells was unknown. Herein, we observed a remarkable decrease of miR-365 expression in CD133 or EpCAM-positive liver CSCs as well as in CSC-enriched hepatoma spheres. Up-regulated miR-365 suppressed liver CSC expansion by inhibiting the dedifferentiation of hepatoma cells and decreasing the self-renewal ability of liver CSCs. Mechanistically, bioinformatic and luciferase reporter analysis identified Ras-related C3 botulinum toxin substrate 1 (RAC1) as a direct target of miR-365. Overexpression of miR-365 in hepatoma cells downregulated the RAC1 mRNA and protein expression. RAC1 also could promote the expansion of liver CSCs. The special RAC1 inhibitor EHop-106 or RAC1 overexpression abolished the discrepancy in liver CSC proportion and the self-renewal capacity between miR-365 overexpression hepatoma cells and control cells, which further confirmed that RAC1 was required in miR-365-suppressed liver CSCs expansion. miR-365 was downregulated in liver CSCs and could inhibit HCC cells dedifferentiation and liver CSCs expansion by targeting RAC1 signaling.

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Section: Mir-365 Suppressed Liver Cscs Expansionsupporting

confidence: 82%

miR‐365 regulates liver cancer stem cells via RAC1 pathway

Jiang

Liu

et al. 2018

Molecular Carcinogenesis

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“…KLF4, one of the well‐known Yamanaka factors, was the other increased protein in three SR HCC cell lines in this study. KLF4 plays pivotal roles in inducing the development of stem cells, inducing normal stem cells, pluripotent stem cells, and CSCs . CSCs are a small subpopulation of cancer cells with self‐renewal and pluripotency abilities.…”

Section: Discussionmentioning

confidence: 99%

“…KLF4 plays pivotal roles in inducing the development of stem cells, inducing normal stem cells, pluripotent stem cells, and CSCs. 11 CSCs are a small subpopulation of cancer cells with self-renewal and pluripotency abilities. A growing number of studies suggest that CSCs are responsible for tumor development, recurrence and metastasis leading to tumor development, progression and mortality.…”

Section: Discussionmentioning

confidence: 99%

Activation of EGFR‐KLF4 positive feedback loop results in acquired resistance to sorafenib in hepatocellular carcinoma

Pang

Yuan

et al. 2019

Molecular Carcinogenesis

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Sorafenib is the standard first‐line systemic chemotherapeutic drugs for advanced hepatocellular carcinoma (HCC), but acquired resistance to sorafenib is frequently observed in clinical practice. In this study, we first produced three sorafenib resistance (SR) HCC cell lines by using two human HCC cell lines (Hep3B and Huh7) and a human primary HCC cell line. We identified that epidermal growth factor receptor (EGFR) and Kruppel‐like factor 4 (KLF4) are dramatically increased in the three SR HCC cell lines. Either inhibition of tyrosine kinase activity of EGFR with Erlotinib/Icotinib or inhibition of KLF4 expression with short hairpin RNA recovered the response of three SR HCC cell lines to sorafenib, suggesting the critical roles of EGFR tyrosine kinase and KLF4 on inducing SR. Luciferase activity and chromatin immunoprecipitation assays further determined that KLF4 promoted EGFR expression through inducing its transcription by directly binding to its promoter. EGFR, conversely, could also promote KLF4 expression through inducing its transcription by binding to its promoter in a tyrosine kinase‐dependent manner, suggesting that a positive feedback loop formed by EGFR and KLF4 further amplifies their effects on inducing SR. Up to now, our findings that KLF4 induces the development of SR and it cooperates with EGFR to form a positive feedback loop to amplify their SR‐inducing abilities have rarely been reported. Our findings bear possible implications for the improvement of the efficacy of sorafenib in HCC.

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“…Finally, we examined the transcription factors Nanog and octamer‐binding transcription factor 4 (Oct4), which are usually expressed in embryonic stem cells, where they are involved in pluripotency regulation, proliferation and renewal. These transcription factors have also been used to detect cancer stem cell subpopulations (Iv Santaliz‐Ruiz et al ., ; van Schaijik et al ., ; Zheng et al ., ). The increased expression of all the genes analysed in sorafenib‐resistant cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

Targeting AMP‐activated kinase impacts hepatocellular cancer stem cells induced by long‐term treatment with sorafenib

et al. 2019

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Hepatocellular carcinoma ( HCC ) is the third leading cause of cancer death worldwide. HCC treatment is hindered by the frequent emergence of chemoresistance to the multikinase inhibitor sorafenib, which has been related to the presence of cancer stem cells ( CSC s) that self‐renew and often escape therapy. The key metabolic sensor AMP ‐activated kinase ( AMPK ) has recently been recognized as a tumour growth regulator. In this study, we aimed to elucidate the role of AMPK in the development of a stem cell phenotype in HCC cells. To this end, we enriched the CSC population in HCC cell lines that showed increased expression of drug resistance ( ALDH 1A1, ABCB 1A) and stem cell ( CD 133, Nanog, Oct4, alpha fetoprotein) markers and demonstrated their stemness phenotype. These cells were refractory to sorafenib‐induced cell death. We report that sorafenib‐resistant cells had lower levels of total and phosphorylated AMPK as well as its downstream substrate, ACC , compared with the parental cells. Interestingly, AMPK knockdown with si RNA or inhibition with dorsomorphin increased the expression of stem cell markers in parental cells and blocked sorafenib‐induced cell death. Conversely, the upregulation of AMPK , either by transfection or by pharmacological activation with A‐769662, decreased the expression of ALDH 1A1, ABCB 1A, CD 133, Nanog, Oct4, and alpha fetoprotein, and restored sensitivity to sorafenib. Analysis of the underlying mechanism points to hypoxia‐inducible factor HIF ‐1α as a regulator of stemness. In vivo studies in a xenograft mouse model demonstrated that stem‐like cells have greater tumourigenic capacity. AMPK activation reduced xenograft tumour growth and decreased the expression of stem cell markers. Taken together, these results indicate that AMPK may serve as a novel target to overcome chemoresistance in HCC .

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Subcellular localisation of the stem cell markers OCT4, SOX2, NANOG, KLF4 and c-MYC in cancer: a review

Cited by 161 publications

References 52 publications

miR‐365 regulates liver cancer stem cells via RAC1 pathway

miR‐365 regulates liver cancer stem cells via RAC1 pathway

Activation of EGFR‐KLF4 positive feedback loop results in acquired resistance to sorafenib in hepatocellular carcinoma

Targeting AMP‐activated kinase impacts hepatocellular cancer stem cells induced by long‐term treatment with sorafenib

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