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Selective Activation of Cancer Stem Cells by Size-Specific Hyaluronan in Head and Neck Cancer.

Shiina M, Bourguignon LY - Int J Cell Biol (2015)

Bottom Line: Survival protein (cIAP-1) expression was also stimulated by 200 kDa-HA in these CSCs leading to cisplatin resistance.Furthermore, our results indicate that the anti-miR-10 inhibitor not only decreases survival protein expression, but also increases chemosensitivity of the 200 kDa-HA-treated CSCs.These findings strongly support the contention that 200 kDa-HA plays a pivotal role in miR-10 production leading to survival protein upregulation and chemoresistance in CSCs.

View Article: PubMed Central - PubMed

Affiliation: San Francisco Veterans Affairs Medical Center and Department of Medicine, University of California at San Francisco and Endocrine Unit (111N2), 4150 Clement Street, San Francisco, CA 94121, USA.

ABSTRACT
We determined that human head and neck cancer cells (HSC-3 cell line) contain a subpopulation displaying cancer stem cell (CSC) properties and are very tumorigenic. Specifically, we investigated whether different sizes of hyaluronan (HA) (e.g., 5 kDa, 20 kDa, 200 kDa, or 700 kDa-HA-sizes) play a role in regulating these CSCs. First, we observed that 200 kDa-HA (but not other sizes of HA) preferentially induces certain stem cell marker expression resulting in self-renewal and clonal formation of these cells. Further analyses indicate that 200 kDa-HA selectively stimulates the expression of a panel of microRNAs (most noticeably miR-10b) in these CSCs. Survival protein (cIAP-1) expression was also stimulated by 200 kDa-HA in these CSCs leading to cisplatin resistance. Furthermore, our results indicate that the anti-miR-10 inhibitor not only decreases survival protein expression, but also increases chemosensitivity of the 200 kDa-HA-treated CSCs. These findings strongly support the contention that 200 kDa-HA plays a pivotal role in miR-10 production leading to survival protein upregulation and chemoresistance in CSCs. Together, our findings suggest that selective activation of oncogenic signaling by certain sizes of HA (e.g., 200 kDa-HA) may be instrumental in the formation of CSC functions leading to tumor cell survival and chemoresistance in head and neck cancer progression.

No MeSH data available.


Related in: MedlinePlus

Analyses of 200 kDa-HA-mediated survival protein (cIAP1) expression in CD44v3highALDHhigh cells. (a) Detection of the expression of cIAP1 by anti-cIAP1-mediated immunoblotting using cell lysate isolated from CD44v3highALDHhigh cells treated with different sizes of HA [e.g., no HA ((A), lane 1), 5 kDa-HA ((A), lane 2), 20 kDa-HA ((A), lane 3), and 200 kDa-HA ((A), lane 4)] for 3 days. (b) Detection of the expression of cIAP1 by anti-cIAP1-mediated immunoblotting using cell lysate isolated from CD44v3highALDHhigh cells transfected with negative miRNA control [treated with no HA ((A), lane 1) or with 200 kDa-HA for 24 h ((A), lane 2)] or treated with anti-miR-10b inhibitor with no HA ((A), lane 3) or with 200 kDa HA addition for 3 days ((A), lane 4). The amount of actin detected by anti-actin-mediated immunoblot ((a): (B), lane 1–4; (b): (B), lane 1–4) in each gel lane was used as a loading control.
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fig6: Analyses of 200 kDa-HA-mediated survival protein (cIAP1) expression in CD44v3highALDHhigh cells. (a) Detection of the expression of cIAP1 by anti-cIAP1-mediated immunoblotting using cell lysate isolated from CD44v3highALDHhigh cells treated with different sizes of HA [e.g., no HA ((A), lane 1), 5 kDa-HA ((A), lane 2), 20 kDa-HA ((A), lane 3), and 200 kDa-HA ((A), lane 4)] for 3 days. (b) Detection of the expression of cIAP1 by anti-cIAP1-mediated immunoblotting using cell lysate isolated from CD44v3highALDHhigh cells transfected with negative miRNA control [treated with no HA ((A), lane 1) or with 200 kDa-HA for 24 h ((A), lane 2)] or treated with anti-miR-10b inhibitor with no HA ((A), lane 3) or with 200 kDa HA addition for 3 days ((A), lane 4). The amount of actin detected by anti-actin-mediated immunoblot ((a): (B), lane 1–4; (b): (B), lane 1–4) in each gel lane was used as a loading control.

Mentions: Survival proteins such as inhibitors of apoptosis proteins (IAPs) are frequently upregulated in CSCs following HA treatment [15]. Importantly, high levels of IAPs in CSCs increase cell survival due to the binding of IAPs to caspases and the suppression of apoptosis [26]. Here, we found that the expression of IAPs such as c-IAP-1 significantly increased in CD44v3highALDH1high cells treated with 200 kDA-HA based on anti-c-IAP-1-mediated immunoblot analyses (Figure 6). There is only a relatively low level of c-IAP-1 expression detected with other sizes of HAs (e.g., 5 kDa-HA, 20 kDa-HA, or no HA treatment) (Figure 6(a)). These findings clearly indicate that the survival proteins such as c-IAP-1 are upregulated in the CD44v3highALDHhigh cell subpopulation isolated from HNSCC (HSC-3) following 200 kDa-HA treatment.


Selective Activation of Cancer Stem Cells by Size-Specific Hyaluronan in Head and Neck Cancer.

Shiina M, Bourguignon LY - Int J Cell Biol (2015)

Analyses of 200 kDa-HA-mediated survival protein (cIAP1) expression in CD44v3highALDHhigh cells. (a) Detection of the expression of cIAP1 by anti-cIAP1-mediated immunoblotting using cell lysate isolated from CD44v3highALDHhigh cells treated with different sizes of HA [e.g., no HA ((A), lane 1), 5 kDa-HA ((A), lane 2), 20 kDa-HA ((A), lane 3), and 200 kDa-HA ((A), lane 4)] for 3 days. (b) Detection of the expression of cIAP1 by anti-cIAP1-mediated immunoblotting using cell lysate isolated from CD44v3highALDHhigh cells transfected with negative miRNA control [treated with no HA ((A), lane 1) or with 200 kDa-HA for 24 h ((A), lane 2)] or treated with anti-miR-10b inhibitor with no HA ((A), lane 3) or with 200 kDa HA addition for 3 days ((A), lane 4). The amount of actin detected by anti-actin-mediated immunoblot ((a): (B), lane 1–4; (b): (B), lane 1–4) in each gel lane was used as a loading control.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4581563&req=5

fig6: Analyses of 200 kDa-HA-mediated survival protein (cIAP1) expression in CD44v3highALDHhigh cells. (a) Detection of the expression of cIAP1 by anti-cIAP1-mediated immunoblotting using cell lysate isolated from CD44v3highALDHhigh cells treated with different sizes of HA [e.g., no HA ((A), lane 1), 5 kDa-HA ((A), lane 2), 20 kDa-HA ((A), lane 3), and 200 kDa-HA ((A), lane 4)] for 3 days. (b) Detection of the expression of cIAP1 by anti-cIAP1-mediated immunoblotting using cell lysate isolated from CD44v3highALDHhigh cells transfected with negative miRNA control [treated with no HA ((A), lane 1) or with 200 kDa-HA for 24 h ((A), lane 2)] or treated with anti-miR-10b inhibitor with no HA ((A), lane 3) or with 200 kDa HA addition for 3 days ((A), lane 4). The amount of actin detected by anti-actin-mediated immunoblot ((a): (B), lane 1–4; (b): (B), lane 1–4) in each gel lane was used as a loading control.
Mentions: Survival proteins such as inhibitors of apoptosis proteins (IAPs) are frequently upregulated in CSCs following HA treatment [15]. Importantly, high levels of IAPs in CSCs increase cell survival due to the binding of IAPs to caspases and the suppression of apoptosis [26]. Here, we found that the expression of IAPs such as c-IAP-1 significantly increased in CD44v3highALDH1high cells treated with 200 kDA-HA based on anti-c-IAP-1-mediated immunoblot analyses (Figure 6). There is only a relatively low level of c-IAP-1 expression detected with other sizes of HAs (e.g., 5 kDa-HA, 20 kDa-HA, or no HA treatment) (Figure 6(a)). These findings clearly indicate that the survival proteins such as c-IAP-1 are upregulated in the CD44v3highALDHhigh cell subpopulation isolated from HNSCC (HSC-3) following 200 kDa-HA treatment.

Bottom Line: Survival protein (cIAP-1) expression was also stimulated by 200 kDa-HA in these CSCs leading to cisplatin resistance.Furthermore, our results indicate that the anti-miR-10 inhibitor not only decreases survival protein expression, but also increases chemosensitivity of the 200 kDa-HA-treated CSCs.These findings strongly support the contention that 200 kDa-HA plays a pivotal role in miR-10 production leading to survival protein upregulation and chemoresistance in CSCs.

View Article: PubMed Central - PubMed

Affiliation: San Francisco Veterans Affairs Medical Center and Department of Medicine, University of California at San Francisco and Endocrine Unit (111N2), 4150 Clement Street, San Francisco, CA 94121, USA.

ABSTRACT
We determined that human head and neck cancer cells (HSC-3 cell line) contain a subpopulation displaying cancer stem cell (CSC) properties and are very tumorigenic. Specifically, we investigated whether different sizes of hyaluronan (HA) (e.g., 5 kDa, 20 kDa, 200 kDa, or 700 kDa-HA-sizes) play a role in regulating these CSCs. First, we observed that 200 kDa-HA (but not other sizes of HA) preferentially induces certain stem cell marker expression resulting in self-renewal and clonal formation of these cells. Further analyses indicate that 200 kDa-HA selectively stimulates the expression of a panel of microRNAs (most noticeably miR-10b) in these CSCs. Survival protein (cIAP-1) expression was also stimulated by 200 kDa-HA in these CSCs leading to cisplatin resistance. Furthermore, our results indicate that the anti-miR-10 inhibitor not only decreases survival protein expression, but also increases chemosensitivity of the 200 kDa-HA-treated CSCs. These findings strongly support the contention that 200 kDa-HA plays a pivotal role in miR-10 production leading to survival protein upregulation and chemoresistance in CSCs. Together, our findings suggest that selective activation of oncogenic signaling by certain sizes of HA (e.g., 200 kDa-HA) may be instrumental in the formation of CSC functions leading to tumor cell survival and chemoresistance in head and neck cancer progression.

No MeSH data available.


Related in: MedlinePlus