Cancer stem cells in hepatocellular carcinoma: Therapeutic implications based on stem cell biology

The therapeutic potential of stem cells is already being harnessed in clinical trails. Of even greater therapeutic potential has been the discovery of mechanisms to reprogram differentiated cells into a pluripotent stem cell-like state known as induced pluripotent stem cells (iPSCs). Stem cell nature is governed and maintained by a hierarchy of transcription factors, the apex of which is OCT4. Although much research has elucidated the transcriptional regulation of OCT4, OCT4 regulated gene expression profiles and OCT4 transcriptional activation mechanisms in both stem cell biology and cellular reprogramming to iPSCs, the fundamental biochemistry surrounding the OCT4 transcription factor remains largely unknown. In order to analyze the biochemical relationship between HSP90 and human OCT4 we developed an exogenous active human OCT4 expression model with human OCT4 under transcriptional control of a constitutive promoter. We identified the direct interaction between HSP90 and human OCT4 despite the fact that the proteins predominantly display differential subcellular localizations. We show that HSP90 inhibition resulted in degradation of human OCT4 via the ubiquitin proteasome degradation pathway. As human OCT4 and HSP90 did not interact in the nucleus, we suggest that HSP90 functions in the cytoplasmic stabilization of human OCT4. Our analysis suggests HSP90 inhibition inhibits the transcriptional activity of human OCT4 dimers without affecting monomeric OCT4 activity. Additionally our data suggests that the HSP90 and human OCT4 complex is modulated by phosphorylation events either promoting or abrogating the interaction between HSP90 and human OCT4. Our data suggest that human OCT4 displays the characteristics describing HSP90 client proteins, therefore we identify human OCT4 as a putative HSP90 client protein. The regulation of the transcription factor OCT4 by HSP90 provides fundamental insights into the complex biochemistry of stem cell biology. This may also be suggestive that HSP90 not only regulates stem cell biology by maintaining routine cellular homeostasis but additionally through the direct regulation of pluripotency factors.

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Toward Personalized Cell Therapies by Using Stem Cells: Seven Relevant Topics for Safety and Success in Stem Cell Therapy

Journal of Biomedicine and Biotechnology ◽

10.1155/2012/758102 ◽

2012 ◽

Vol 2012 ◽

pp. 1-12 ◽

Cited By ~ 8

Author(s):

Fernando de Sá Silva ◽

Paula Nascimento Almeida ◽

João Vitor Paes Rettore ◽

Claudinéia Pereira Maranduba ◽

Camila Maurmann de Souza ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Cell Therapy ◽

Cell Biology ◽

Stem Cell Biology ◽

Controversial Issues ◽

Immunosuppressive Activity ◽

Cell Therapies ◽

Tumorigenic Potential ◽

Wide Range

Stem cells, both embryonic and adult, due to the potential for application in tissue regeneration have been the target of interest to the world scientific community. In fact, stem cells can be considered revolutionary in the field of medicine, especially in the treatment of a wide range of human diseases. However, caution is needed in the clinical application of such cells and this is an issue that demands more studies. This paper will discuss some controversial issues of importance for achieving cell therapy safety and success. Particularly, the following aspects of stem cell biology will be presented: methods for stem cells culture, teratogenic or tumorigenic potential, cellular dose, proliferation, senescence, karyotyping, and immunosuppressive activity.

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Loss of miR-100 and miR-125b results in cancer stem cell properties through IGF2 upregulation in hepatocellular carcinoma

Scientific Reports ◽

10.1038/s41598-020-77960-9 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Hyang Sook Seol ◽

Yoshimitsu Akiyama ◽

San-Eun Lee ◽

Shu Shimada ◽

Se Jin Jang

Keyword(s):

Hepatocellular Carcinoma ◽

Stem Cells ◽

Stem Cell ◽

Cancer Stem Cells ◽

Xenograft Model ◽

Mtor Pathway ◽

Carcinoma Cells ◽

Stable Cell Line ◽

Hep3b Cells ◽

Igf2 Expression

AbstractStemness factors control microRNA expression in cancer stem cells. Downregulation of miR-100 and miR-125b is associated with tumor progression and prognosis of various cancers. Comparing miRNA profiling of patient-derived tumorsphere (TS) and adherent (2D) hepatocellular carcinoma cells, miR-100 and miR-125b are identified to have association with stemness. In TS cells, miR-100 and miR-125b were downregulated comparing to 2D cells. The finding was reproduced in Hep3B cells. Overexpression of stemness factors NANOG, OCT4 and SOX2 by introduction of gene constructs in Hep3B cells suppressed these two miRNA expression levels. Treatment of chromeceptin, an IGF signaling pathway inhibitor, decreased numbers of TS and inhibited the AKT/mTOR pathway. Stable cell line of miR-100 and miR-125b overexpression decreased IGF2 expression and inhibited tumor growth in the xenograft model. In conclusion, miR-100 and miR-125b have tumor suppressor role in hepatocellular carcinoma through inhibiting IGF2 expression and activation of the AKT/mTOR pathway.

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Realistic Prospects for Stem Cell Therapeutics

Hematology ◽

10.1182/asheducation-2003.1.398 ◽

2003 ◽

Vol 2003 (1) ◽

pp. 398-418 ◽

Cited By ~ 52

Author(s):

George Q. Daley ◽

Margaret A. Goodell ◽

Evan Y. Snyder

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Regenerative Medicine ◽

Cell Biology ◽

Adult Stem Cells ◽

Stem Cell Biology ◽

Cell Therapies ◽

The Media ◽

New Treatment ◽

Definition Of

Abstract Studies of the regenerating hematopoietic system have led to the definition of many of the fundamental principles of stem cell biology. Therapies based on a range of tissue stem cells have been widely touted as a new treatment modality, presaging an emerging new specialty called regenerative medicine that promises to harness stem cells from embryonic and somatic sources to provide replacement cell therapies for genetic, malignant, and degenerative conditions. Insights borne from stem cell biology also portend development of protein and small molecule therapeutics that act on endogenous stem cells to promote repair and regeneration. Much of the newfound enthusiasm for regenerative medicine stems from the hope that advances in the laboratory will be followed soon thereafter by breakthrough treatments in the clinic. But how does one sort through the hype to judge the true promise? Are stem cell biologists and the media building expectations that cannot be met? Which diseases can be treated, and when can we expect success? In this review, we outline the realms of investigation that are capturing the most attention, and consider the current state of scientific understanding and controversy regarding the properties of embryonic and somatic (adult) stem cells. Our objective is to provide a framework for appreciating the promise while at the same time understanding the challenges behind translating fundamental stem cell biology into novel clinical therapies.

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