Heterogeneous matrix stiffness regulates the cancer stem-like cell phenotype in hepatocellular carcinoma
© 2022. The Author(s)..
BACKGROUND: Solid tumors are stiffer than their surrounding normal tissues; however, their interior stiffness is not uniform. Under certain conditions, cancer cells can acquire stem-like phenotypes. However, it remains unclear how the heterogeneous physical microenvironment affects stemness expression in cancer cells. Here, we aimed to evaluate matrix stiffness heterogeneity in hepatocellular carcinoma (HCC) tissues and to explore the regulation effect of the tumor microenvironment on stem-like phenotypic changes through mechanical transduction.
METHODS: First, we used atomic force microscopy (AFM) to evaluate the elastic modulus of HCC tissues. We then used hydrogel with adjustable stiffness to investigate the effect of matrix stiffness on the stem-like phenotype expression of HCC cells. Moreover, cells cultured on hydrogel with different stiffness were subjected to morphology, real-time PCR, western blotting, and immunofluorescence analyses to explore the mechanotransduction pathway. Finally, animal models were used to validate in vitro results.
RESULTS: AFM results confirmed the heterogenous matrix stiffness in HCC tissue. Cancer cells adhered to hydrogel with varying stiffness (1.10 ± 0.34 kPa, 4.47 ± 1.19 kPa, and 10.61 kPa) exhibited different cellular and cytoskeleton morphology. Higher matrix stiffness promoted the stem-like phenotype expression and reduced sorafenib-induced apoptosis. In contrast, lower stiffness induced the expression of proliferation-related protein Ki67. Moreover, mechanical signals were transmitted into cells through the integrin-yes-associated protein (YAP) pathway. Higher matrix stiffness did not affect YAP expression, however, reduced the proportion of phosphorylated YAP, promoted YAP nuclear translocation, and regulated gene transcription. Finally, application of ATN-161 (integrin inhibitor) and verteporfin (YAP inhibitor) effectively blocked the stem-like phenotype expression regulated by matrix stiffness.
CONCLUSIONS: Our experiments provide new insights into the interaction between matrix stiffness, cancer cell stemness, and heterogeneity, while also providing a novel HCC therapeutic strategy.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2022 |
|---|---|
| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:20 |
|---|---|
| Enthalten in: |
Journal of translational medicine - 20(2022), 1 vom: 03. Dez., Seite 555 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Wei, Jiayun [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Cancer cell stemness |
|---|
| Anmerkungen: |
Date Completed 06.12.2022 Date Revised 21.12.2022 published: Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1186/s12967-022-03778-w |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM349758093 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM349758093 | ||
| 003 | DE-627 | ||
| 005 | 20231226043405.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2022 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1186/s12967-022-03778-w |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1165.xml |
| 035 | |a (DE-627)NLM349758093 | ||
| 035 | |a (NLM)36463272 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Wei, Jiayun |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Heterogeneous matrix stiffness regulates the cancer stem-like cell phenotype in hepatocellular carcinoma |
| 264 | 1 | |c 2022 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 06.12.2022 | ||
| 500 | |a Date Revised 21.12.2022 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2022. The Author(s). | ||
| 520 | |a BACKGROUND: Solid tumors are stiffer than their surrounding normal tissues; however, their interior stiffness is not uniform. Under certain conditions, cancer cells can acquire stem-like phenotypes. However, it remains unclear how the heterogeneous physical microenvironment affects stemness expression in cancer cells. Here, we aimed to evaluate matrix stiffness heterogeneity in hepatocellular carcinoma (HCC) tissues and to explore the regulation effect of the tumor microenvironment on stem-like phenotypic changes through mechanical transduction | ||
| 520 | |a METHODS: First, we used atomic force microscopy (AFM) to evaluate the elastic modulus of HCC tissues. We then used hydrogel with adjustable stiffness to investigate the effect of matrix stiffness on the stem-like phenotype expression of HCC cells. Moreover, cells cultured on hydrogel with different stiffness were subjected to morphology, real-time PCR, western blotting, and immunofluorescence analyses to explore the mechanotransduction pathway. Finally, animal models were used to validate in vitro results | ||
| 520 | |a RESULTS: AFM results confirmed the heterogenous matrix stiffness in HCC tissue. Cancer cells adhered to hydrogel with varying stiffness (1.10 ± 0.34 kPa, 4.47 ± 1.19 kPa, and 10.61 kPa) exhibited different cellular and cytoskeleton morphology. Higher matrix stiffness promoted the stem-like phenotype expression and reduced sorafenib-induced apoptosis. In contrast, lower stiffness induced the expression of proliferation-related protein Ki67. Moreover, mechanical signals were transmitted into cells through the integrin-yes-associated protein (YAP) pathway. Higher matrix stiffness did not affect YAP expression, however, reduced the proportion of phosphorylated YAP, promoted YAP nuclear translocation, and regulated gene transcription. Finally, application of ATN-161 (integrin inhibitor) and verteporfin (YAP inhibitor) effectively blocked the stem-like phenotype expression regulated by matrix stiffness | ||
| 520 | |a CONCLUSIONS: Our experiments provide new insights into the interaction between matrix stiffness, cancer cell stemness, and heterogeneity, while also providing a novel HCC therapeutic strategy | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Cancer cell stemness | |
| 650 | 4 | |a Hepatocellular carcinoma | |
| 650 | 4 | |a Heterogeneity | |
| 650 | 4 | |a Matrix stiffness | |
| 650 | 4 | |a Yes-associated protein | |
| 650 | 7 | |a Hydrogels |2 NLM | |
| 700 | 1 | |a Yao, Jia |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Chendong |e verfasserin |4 aut | |
| 700 | 1 | |a Mao, Yongcui |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Dan |e verfasserin |4 aut | |
| 700 | 1 | |a Xie, Ye |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Pinyan |e verfasserin |4 aut | |
| 700 | 1 | |a Yan, Mengchao |e verfasserin |4 aut | |
| 700 | 1 | |a Ren, Longfei |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Yan |e verfasserin |4 aut | |
| 700 | 1 | |a Zheng, Qiuxia |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Xun |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Journal of translational medicine |d 2003 |g 20(2022), 1 vom: 03. Dez., Seite 555 |w (DE-627)NLM142679194 |x 1479-5876 |7 nnns |
| 773 | 1 | 8 | |g volume:20 |g year:2022 |g number:1 |g day:03 |g month:12 |g pages:555 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1186/s12967-022-03778-w |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 20 |j 2022 |e 1 |b 03 |c 12 |h 555 | ||