Integrin α6 (CD49f), The Microenvironment and Cancer Stem Cells

Bigoni-Ordóñez, Gabriele D; Czarnowski, Daniel; Parsons, Tyler; Madlambayan, Gerard J.; Villa‐Diaz, Luis G.

doi:10.2174/1574888x13666181002151330

Cited by 30 publications

(20 citation statements)

References 93 publications

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“…Both of these integrins are cell adhesion molecules that are vital to signalling pathways that regulate tumour development, metastasis, and angiogenesis [38,39]. Several lines of evidence demonstrate that ITGA6 is a putative stemness marker [[40], [41], [42], [43]], and aberrant expression of ITGA6 has been shown to play an important role in the development and progression of various types of cancers [29,[44], [45], [46]]. Notably, the expression of ITGA6 is significantly associated with the incidence of intravesical recurrence [47].…”

Section: Discussionmentioning

confidence: 99%

N6-methyladenosine modification of ITGA6 mRNA promotes the development and progression of bladder cancer

et al. 2019

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BackgroundAccumulating evidence has revealed the critical roles of N6-methyladenosine (m6A) modification of mRNA in various cancers. However, the biological function and regulation of m6A in bladder cancer (BC) are not yet fully understood.MethodsWe performed cell phenotype analysis and established in vivo mouse xenograft models to assess the effects of m6A-modified ITGA6 on BC growth and progression. Methylated RNA immunoprecipitation (MeRIP), RNA immunoprecipitation and luciferase reporter and mutagenesis assays were used to define the mechanism of m6A-modified ITGA6. Immunohistochemical analysis was performed to assess the correlation between METTL3 and ITGA6 expression in bladder cancer patients.FindingsWe show that the m6A writer METTL3 and eraser ALKBH5 altered cell adhesion by regulating ITGA6 expression in bladder cancer cells. Moreover, upregulation of ITGA6 is correlated with the increase in METTL3 expression in human BC tissues, and higher expression of ITGA6 in patients indicates a lower survival rate. Mechanistically, m6A is highly enriched within the ITGA6 transcripts, and increased m6A methylations of the ITGA6 mRNA 3’UTR promotes the translation of ITGA6 mRNA via binding of the m6A readers YTHDF1 and YTHDF3. Inhibition of ITGA6 results in decreased growth and progression of bladder cancer cells in vitro and in vivo. Furthermore, overexpression of ITGA6 in METTL3-depleted cells partially restores the BC adhesion, migration and invasion phenotypes.InterpretationOur results demonstrate an oncogenic role of m6A-modified ITGA6 and show its regulatory mechanisms in BC development and progression, thus identifying a potential therapeutic target for BC.FundThis work was supported by National Natural Science Foundation of China (81772699, 81472999).

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Section: Discussionmentioning

confidence: 99%

N6-methyladenosine modification of ITGA6 mRNA promotes the development and progression of bladder cancer

et al. 2019

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“…Blaber et al 8 also reported that multiple markers indicative of self-renewal of stem cells were increased under sµg. We previously identified integrin α6 (also known as CD49f and ITGA6) as a key regulator in the self-renewal of hPSCs 38 and as the only common stem cell-related protein expressed in all 35 identified stem cell types 39 , 46 . Here, we also observed that sµg upregulates the expression of pluripotent TFs and integrin α6 both at gene and protein levels in hPSCs in comparison to the 1g control group.…”

Section: Discussionmentioning

confidence: 99%

Enhanced self-renewal of human pluripotent stem cells by simulated microgravity

et al. 2022

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A systematic study on the biological effects of simulated microgravity (sµg) on human pluripotent stem cells (hPSC) is still lacking. Here, we used a fast-rotating 2-D clinostat to investigate the sµg effect on proliferation, self-renewal, and cell cycle regulation of hPSCs. We observed significant upregulation of protein translation of pluripotent transcription factors in hPSC cultured in sµg compared to cells cultured in 1g conditions. In addition to a significant increase in expression of telomere elongation genes. Differentiation experiments showed that hPSC cultured in sµg condition were less susceptible to differentiation compared to cells in 1g conditions. These results suggest that sµg enhances hPSC self-renewal. Our study revealed that sµg enhanced the cell proliferation of hPSCs by regulating the expression of cell cycle-associated kinases. RNA-seq analysis indicated that in sµg condition the expression of differentiation and development pathways are downregulated, while multiple components of the ubiquitin proteasome system are upregulated, contributing to an enhanced self-renewal of hPSCs. These effects of sµg were not replicated in human fibroblasts. Taken together, our results highlight pathways and mechanisms in hPSCs vulnerable to microgravity that imposes significant impacts on human health and performance, physiology, and cellular and molecular processes.

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“…The integrin subunit a6 (coded by the gene ITGA6 ) has received considerable attention, especially for its role in regulating cancer stem-like cells [ 19 , 20 ]. Integrin a6 dimerizes with integrin b1 or b4 to generate the surface receptor for laminin.…”

Section: Introductionmentioning

confidence: 99%

Dual Role of Integrin Alpha-6 in Glioblastoma: Supporting Stemness in Proneural Stem-Like Cells While Inducing Radioresistance in Mesenchymal Stem-Like Cells

Stanzani

Pedrosa

Bourmeau

et al. 2021

Cancers

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Therapeutic resistance after multimodal therapy is the most relevant cause of glioblastoma (GBM) recurrence. Extensive cellular heterogeneity, mainly driven by the presence of GBM stem-like cells (GSCs), strongly correlates with patients’ prognosis and limited response to therapies. Defining the mechanisms that drive stemness and control responsiveness to therapy in a GSC-specific manner is therefore essential. Here we investigated the role of integrin a6 (ITGA6) in controlling stemness and resistance to radiotherapy in proneural and mesenchymal GSCs subtypes. Using cell sorting, gene silencing, RNA-Seq, and in vitro assays, we verified that ITGA6 expression seems crucial for proliferation and stemness of proneural GSCs, while it appears not to be relevant in mesenchymal GSCs under basal conditions. However, when challenged with a fractionated protocol of radiation therapy, comparable to that used in the clinical setting, mesenchymal GSCs were dependent on integrin a6 for survival. Specifically, GSCs with reduced levels of ITGA6 displayed a clear reduction of DNA damage response and perturbation of cell cycle pathways. These data indicate that ITGA6 inhibition is able to overcome the radioresistance of mesenchymal GSCs, while it reduces proliferation and stemness in proneural GSCs. Therefore, integrin a6 controls crucial characteristics across GBM subtypes in GBM heterogeneous biology and thus may represent a promising target to improve patient outcomes.

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Integrin α6 (CD49f), The Microenvironment and Cancer Stem Cells

Cited by 30 publications

References 93 publications

N6-methyladenosine modification of ITGA6 mRNA promotes the development and progression of bladder cancer

N6-methyladenosine modification of ITGA6 mRNA promotes the development and progression of bladder cancer

Enhanced self-renewal of human pluripotent stem cells by simulated microgravity

Dual Role of Integrin Alpha-6 in Glioblastoma: Supporting Stemness in Proneural Stem-Like Cells While Inducing Radioresistance in Mesenchymal Stem-Like Cells

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