scholarly journals The m6A Methylation-Regulated AFF4 Promotes Self-Renewal of Bladder Cancer Stem Cells

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Qian Gao ◽  
Jin Zheng ◽  
Zegui Ni ◽  
Pengli Sun ◽  
Congcong Yang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bladder Cancer ◽  
Cancer Stem Cells ◽  
Cell Fate ◽  
Biological Functions ◽  
Aldh Activity ◽  
Promoter Regions ◽  
Self Renewal ◽  
Signaling Axis

The dynamic N6-methyladenosine (m6A) modification of mRNA plays a role in regulating gene expression and determining cell fate. However, the functions of m6A mRNA modification in bladder cancer stem cells (BCSCs) have not been described. Here, we show that global RNA m6A abundance and the expression of m6A-forming enzyme METTL3 are higher in BCSCs than those in non-CSCs of bladder cancer (BCa) cells. The depletion of the METTL3 inhibited the self-renewal of BCSCs, as evidenced by decreased ALDH activity and sphere-forming ability. Mechanistically, METTL3 regulates the m6A modification and thereby the expression of AF4/FMR2 family member 4 (AFF4), knockdown of which phenocopies the METTL3 ablation and diminishes the tumor-initiating capability of BCSCs in vivo. AFF4 binds to the promoter regions and sustains the transcription of SOX2 and MYC which have critical biological functions in BCSCs. Collectively, our results demonstrate the critical roles of m6A modification in self-renewal and tumorigenicity of BCSCs through a novel signaling axis of METTL3-AFF4-SOX2/MYC.

scholarly journals MicroRNA-28-5p Regulates Liver Cancer Stem Cell Expansion via IGF-1 Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-16 ◽  
Author(s):  
Qing Xia ◽  
Tao Han ◽  
Pinghua Yang ◽  
Ruoyu Wang ◽  
Hengyu Li ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Liver Cancer ◽  
Critical Role ◽  
Self Renewal ◽  
Sorafenib Treatment ◽  
The Impact

Background. MicroRNAs (miRNAs) play a critical role in the regulation of cancer stem cells (CSCs). However, the role of miRNAs in liver CSCs has not been fully elucidated. Methods. Real-time PCR was used to detect the expression of miR-miR-28-5p in liver cancer stem cells (CSCs). The impact of miR-28-5p on liver CSC expansion was investigated both in vivo and in vitro. The correlation between miR-28-5p expression and sorafenib benefits in HCC was further evaluated in patient-derived xenografts (PDXs). Results. Our data showed that miR-28-5p was downregulated in sorted EpCAM- and CD24-positive liver CSCs. Biofunctional investigations revealed that knockdown miR-28-5p promoted liver CSC self-renewal and tumorigenesis. Consistently, miR-28-5p overexpression inhibited liver CSC’s self-renewal and tumorigenesis. Mechanistically, we found that insulin-like growth factor-1 (IGF-1) was a direct target of miR-28-5p in liver CSCs, and the effects of miR-28-5p on liver CSC’s self-renewal and tumorigenesis were dependent on IGF-1. The correlation between miR-28-5p and IGF-1 was confirmed in human HCC tissues. Furthermore, the miR-28-5p knockdown HCC cells were more sensitive to sorafenib treatment. Analysis of patient-derived xenografts (PDXs) further demonstrated that the miR-28-5p may predict sorafenib benefits in HCC patients. Conclusion. Our findings revealed the crucial role of the miR-28-5p in liver CSC expansion and sorafenib response, rendering miR-28-5p an optimal therapeutic target for HCC.

scholarly journals Cancer stem cells enrichment with surface markers CD271 and CD44 in human head and neck squamous cell carcinomas

2019 ◽  
Vol 41 (4) ◽  
pp. 458-466 ◽  
Author(s):  
Osama A Elkashty ◽  
Ghada Abu Elghanam ◽  
Xinyun Su ◽  
Younan Liu ◽  
Peter J Chauvin ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Head And Neck ◽  
Cell Lines ◽  
Squamous Cell ◽  
Colony Formation ◽  
Self Renewal ◽  
Tissue Samples ◽  
Hnscc Cell

Abstract Head and neck squamous cell carcinoma (HNSCC) has a poor 5-year survival rate of 50%. One potential reason for treatment failure is the presence of cancer stem cells (CSCs). Several cell markers, particularly CD44, have been used to isolate CSCs. However, isolating a pure population of CSC in HNSCC still remains a challenging task. Recent findings show that normal oral stem cells were isolated using CD271 as a marker. Thus, we investigated the combined use of CD271 and CD44 to isolate an enriched subpopulation of CSCs, followed by their characterization in vitro, in vivo, and in patients’ tissue samples. Fluorescent-activated cell sorting was used to isolate CD44+/CD271+ and CD44+/CD271− from two human HNSCC cell lines. Cell growth and self-renewal were measured with MTT and sphere/colony formation assays. Treatment-resistance was tested against chemotherapy (cisplatin and 5-fluorouracil) and ionizing radiation. Self-renewal, resistance, and stemness-related genes expression were measured with qRT-PCR. In vivo tumorigenicity was tested with an orthotopic immunodeficient mouse model of oral cancer. Finally, we examined the co-localization of CD44+/CD271+ in patients’ tissue samples. We found that CD271+ cells were a subpopulation of CD44+ cells in human HNSCC cell lines and tissues. CD44+/CD271+ cells exhibited higher cell proliferation, sphere/colony formation, chemo- and radio-resistance, upregulation of CSCs-related genes, and in vivo tumorigenicity when compared to CD44+/CD271− or the parental cell line. These cell markers showed increased expression in patients with the increase of the tumor stage. In conclusion, using both CD44 and CD271 allowed the isolation of CSCs from HNSCC. These enriched CSCs will be more relevant in future treatment and HNSCC progression studies.

scholarly journals Stemness-Attenuating miR-503-3p as a Paracrine Factor to Regulate Growth of Cancer Stem Cells

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Minkoo Seo ◽  
Seung Min Kim ◽  
Eun Young Woo ◽  
Ki-Cheol Han ◽  
Eun Joo Park ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Tumor Growth ◽  
Cellular Heterogeneity ◽  
Paracrine Factor ◽  
Adipose Stem Cell ◽  
Self Renewal ◽  
Human Adipose Stem Cell ◽  
Pluripotency Genes

Cancer stem cells (CSCs) with self-renewal abilities endorse cellular heterogeneity, resulting in metastasis and recurrence. However, there are no promising therapeutics directed against CSCs. Herein, we found that miR-503-3p inhibited tumor growth via the regulation of CSC proliferation and self-renewal. miR-503-3p, isolated from human adipose stem cell- (ASC-) derived exosomes, suppressed initiation and progression of CSCs as determined by anchorage-dependent (colony formation) and anchorage-independent (tumorsphere formation) assays. The expression of pluripotency genes was significantly decreased in miR-503-3p-treated CSCs. Furthermore, xenografts, which received miR-503-3p, exhibited remarkably reduced tumor growth in vivo. Thus, miR-503-3p may function as a stemness-attenuating factor via cell-to-cell communications.

Aldehyde dehydrogenase activity in serous ovarian carcinoma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e15577-e15577
Author(s):  
Petra M. Bareiss ◽  
Tanja N. Fehm ◽  
Anna Fischer ◽  
Matthias Grauer ◽  
Philipp Kokorsch ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Ovarian Carcinoma ◽  
Aldehyde Dehydrogenase ◽  
Cell Cycle Distribution ◽  
Aldh Activity ◽  
Serous Ovarian Carcinoma ◽  
Aldh1 Expression

e15577 Background: Only specific subpopulations of tumor cells, so called cancer stem cells (CSC) may initiate and maintain tumors. The phenotype and molecular properties of ovarian CSC remain elusive. Aldehyde dehydrogenase (ALDH) activity characterizes (cancer) stem cells in different tissues and has been associated with ovarian CSC (Silva et al, 2011; Kryczek et al, 2012). Contradictory results have been reported on ALDH1 expression and prognosis in ovarian carcinoma. In this study, we explore the role of ALDH in serous ovarian carcinoma (SOC). Methods: Aldefluor-staining was used to assess ALDH activity in different ovarian carcinoma cell-lines and patient samples. ALDH+ and ALDH- cells isolated by FACS and ALDH1 versus control siRNA treated cells were analyzed in sphere forming, proliferation, BrdU and cell cycle assays. In vivo tumorigenicity assays including serial re-transplantations were performed in NOD/SCID/IL2Rγnull mice. ALDH1 and Ki67 expression were assessed immunohistochemically on a tissue microarray of 152 SOC samples. Results: ALDH+ cells formed more tumor spheres than ALDH- cells from the OVCAR-3 cell line and primary SOC and larger spheres (> 5.000 µm²) developed solely from ALDH+ cells. However, in vivo both cell fractions gave rise to tumors. Tumors contained both ALDH+ and ALDH- cells irrespective of the starting population. Notably, ALDH+ cells generated tumors more rapidly and induced larger tumors, suggesting a higher proliferative capacity. Immunohistochemical analysis of a larger cohort of SOC patients confirmed association of ALDH1 expression with the proliferation marker Ki67 (p=0.007). Surprisingly, co-stainings revealed that ALDH1 positive cells were mostly Ki67 negative and cell cycle synchronisation experiments using different agents showed ALDH induction in G0-enriched OVCAR-3 cells. However, inhibition of ALDH by treatment with three distinct siRNAs against ALDH1 did not alter cell cycle distribution. Conclusions: Our data suggest that ALDH is a correlative marker indicating, but not actively sustaining a quiescent stem-cell like state in SOC. Upon exit from G0, ALDH+ cells lose ALDH expression and induce a proliferative response.

Hematopoietic Development from Human Embryonic Stem Cells

Hematology ◽  
2007 ◽  
Vol 2007 (1) ◽  
pp. 11-16 ◽  
Author(s):  
Mickie Bhatia
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Cell Fate ◽  
Human Embryonic Stem Cells ◽  
Embryonic Stem ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Immunodeficient Mice ◽  
Cell Based Therapy

Abstract The most common human cell-based therapy applied today is hematopoietic stem cell (HSC) transplantation. HSCs can be defined by two essential properties: self-renewal and multilineage hematopoietic differentiation. These combined HSC properties allow them to differentiate into all blood cell types (multilineage) in a sustained manner for the lifetime of the animal, which requires their ability to make cellular copies of themselves (self-renewal). These features can be tested by transplantation from donor to recipient and provide a functional basis to define and identify HSCs. Currently, human bone marrow (BM), mobilized peripheral blood, and umbilical cord blood (CB) represent the major sources of transplantable HSCs, but their availability for use is limited by both quantity and compatibility. Although increasing evidence suggests that somatic HSCs can be expanded to meet current needs, their in vivo potential is concomitantly compromised after ex vivo culture. Pluripotent human embryonic stem cells (hESCs) may provide an alternative. hESCs possess indefinite proliferative capacity in vitro, and have been shown to differentiate into the hematopoietic cell fate, giving rise to erythroid, myeloid, and lymphoid lineages using a variety of differentiation procedures. In most cases, hESC-derived hematopoietic cells show similar clonogenic progenitor capacity and primitive phenotype to somatic sources of hematopoietic progenitors, but possess limited in vivo repopulating capacity when transplanted into immunodeficient mice. Although this suggests HSC function can be derived from hESCs, the efficiency and quality of these cells must be characterized using surrogate models for potential clinical applications.

scholarly journals Long non-coding RNA NORAD promotes pancreatic cancer stem cell proliferation and self-renewal by blocking microRNA-202-5p-mediated ANP32E inhibition

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Yu-Shui Ma ◽  
Xiao-Li Yang ◽  
Yu-Shan Liu ◽  
Hua Ding ◽  
Jian-Jun Wu ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cell Viability ◽  
Luciferase Reporter ◽  
Cell Cycle Distribution ◽  
Loss Of Function ◽  
Self Renewal

Abstract Background Cancer stem cells (CSCs) are key regulators in the processes of tumor initiation, progression, and recurrence. The mechanism that maintains their stemness remains enigmatic, although the role of several long noncoding RNAs (lncRNAs) has been highlighted in the pancreatic cancer stem cells (PCSCs). In this study, we first established that PCSCs overexpressing lncRNA NORAD, and then investigated the effects of NORAD on the maintenance of PCSC stemness. Methods Expression of lncRNA NORAD, miR-202-5p and ANP32E in PC tissues and cell lines was quantified after RNA isolation. Dual-luciferase reporter assay, RNA pull-down and RIP assays were performed to verify the interactions among NORAD, miR-202-5p and ANP32E. We then carried out gain- and loss-of function of miR-202-5p, ANP32E and NORAD in PANC-1 cell line, followed by measurement of the aldehyde dehydrogenase activity, cell viability, apoptosis, cell cycle distribution, colony formation, self-renewal ability and tumorigenicity of PC cells. Results LncRNA NORAD and ANP32E were upregulated in PC tissues and cells, whereas the miR-202-5p level was down-regulated. LncRNA NORAD competitively bound to miR-202-5p, and promoted the expression of the miR-202-5p target gene ANP32E thereby promoting PC cell viability, proliferation, and self-renewal ability in vitro, as well as facilitating tumorigenesis of PCSCs in vivo. Conclusion Overall, lncRNA NORAD upregulates ANP32E expression by competitively binding to miR-202-5, which accelerates the proliferation and self-renewal of PCSCs.

scholarly journals Cancer Stem Cells and Macrophages: Implications in Tumor Biology and Therapeutic Strategies

2016 ◽  
Vol 2016 ◽  
pp. 1-15 ◽  
Author(s):  
Bruno Sainz ◽  
Emily Carron ◽  
Mireia Vallespinós ◽  
Heather L. Machado
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cross Talk ◽  
Tumor Biology ◽  
Cell Types ◽  
Tumor Formation ◽  
Self Renewal ◽  
Numerous Cell ◽  
Key Drivers

Cancer stem cells (CSCs) are a unique subset of cells within tumors with stemlike properties that have been proposed to be key drivers of tumor initiation and progression. CSCs are functionally defined by their unlimited self-renewal capacity and their ability to initiate tumor formationin vivo. Like normal stem cells, CSCs exist in a cellular niche comprised of numerous cell types including tumor-associated macrophages (TAMs) which provides a unique microenvironment to protect and promote CSC functions. TAMs provide pivotal signals to promote CSC survival, self-renewal, maintenance, and migratory ability, and in turn, CSCs deliver tumor-promoting cues to TAMs that further enhance tumorigenesis. Studies in the last decade have aimed to understand the molecular mediators of CSCs and TAMs, and recent advances have begun to elucidate the complex cross talk that occurs between these two cell types. In this review, we discuss the molecular interactions that define CSC-TAM cross talk at each stage of tumor progression and examine the clinical implications of targeting these interactions.

scholarly journals Chemosensitization of prostate cancer stem cells in mice by angiogenin and plexin-B2 inhibitors

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Shuping Li ◽  
Kevin A. Goncalves ◽  
Baiqing Lyu ◽  
Liang Yuan ◽  
Guo-fu Hu
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Ribosomal Rna ◽  
Protein Translation ◽  
Chemotherapeutic Agents ◽  
Self Renewal ◽  
5S Ribosomal Rna ◽  
Prostate Cancer Stem Cells

AbstractCancer stem cells (CSCs) are an obstacle in cancer therapy and are a major cause of drug resistance, cancer recurrence, and metastasis. Available treatments, targeting proliferating cancer cells, are not effective in eliminating quiescent CSCs. Identification of CSC regulators will help design therapeutic strategies to sensitize drug-resistant CSCs for chemo-eradication. Here, we show that angiogenin and plexin-B2 regulate the stemness of prostate CSCs, and that inhibitors of angiogenin/plexin-B2 sensitize prostate CSCs to chemotherapy. Prostate CSCs capable of self-renewal, differentiation, and tumor initiation with a single cell inoculation were identified and shown to be regulated by angiogenin/plexin-B2 that promotes quiescence and self-renewal through 5S ribosomal RNA processing and generation of the bioactive 3′-end fragments of 5S ribosomal RNA, which suppress protein translation and restrict cell cycling. Monoclonal antibodies of angiogenin and plexin-B2 decrease the stemness of prostate CSCs and sensitize them to chemotherapeutic agents in vitro and in vivo.

Cell Cycle Regulation and Cell Fate Decisions in Hematopoietic Stem Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1349-1349
Author(s):  
Emmanuelle Passegue ◽  
Amy J. Wagers ◽  
Sylvie Giuriato ◽  
Wade C. Anderson ◽  
Irving L. Weissman
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Cell Fate ◽  
Cell Cycle Regulation ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Cell Fate Decisions ◽  
Cycle Regulation

Abstract The blood is a perpetually renewing tissue seeded by a rare population of adult bone marrow hematopoietic stem cells (HSC). During steady-state hematopoiesis, the HSC population is relatively quiescent but constantly maintains a low numbers of cycling cells that differentiate to produce the various lineage of mature blood cells. However, in response to hematological stress, the entire HSC population can be recruited into cycle to self-renew and regenerate the blood-forming system. HSC proliferation is therefore highly adaptative and requires appropriate regulation of cell cycle progression to drive both differentiation-associated and self-renewal-associated proliferation, without depletion of the stem cell pool. Although the molecular events controlling HSC proliferation are still poorly understood, they are likely determined, at least in part, by regulated expression and/or function of components and regulators of the cell cycle machinery. Here, we demonstrate that the long-term self-renewing HSC (defined as Lin−/c-Kit+/Sca-1+/Thy1.1int/Flk2−) exists in two distinct states that are both equally important for their in vivo functions as stem cells: a numerically dominant quiescent state, which is critical for HSC function in hematopoietic reconstitution; and a proliferative state, which represents almost a fourth of this population and is essential for HSC functions in differentiation and self-renewal. We show that when HSC exit quiescence and enter G1 as a prelude to cell division, at least two critical events occur: first, during the G1 and subsequent S-G2/M phases, they temporarily lose efficient in vivo engraftment activity, while retaining in vitro differentiation potential; and second, they select the particular cell cycle proteins that are associated with specific developmental outcomes (self-renewal vs. differentiation) and developmental fates (myeloid vs. lymphoid). Together, these findings provide a direct link between HSC proliferation, cell cycle regulation and cell fate decisions that have critical implications for both the therapeutic use of HSC and the understanding of leukemic transformation.

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