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STAT3 mediates ECM stiffness-dependent progression in ovarian cancer

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Abstract

The treatment of ovarian cancer remains a medical challenge and its malignant progression is connected with obvious changes in both tissue and cell stiffness. However, the accurate mechanical-responsive molecules and mechanism remains unclear in ovarian cancer. Based on our previous results combined with the crucial regulatory role of STAT3 in the malignant progression of various cancer types, we want to investigate the relationship between STAT3 and matrix stiffness in ovarian cancer and further explore the potential mechanisms. Collagen-coated polyacrylamide gels (1, 6, and 60 kPa) were prepared to mimic soft or hard matrix stiffness. Western blotting, qRT-PCR, flow cytometry, IHC, EdU assays, and TEM were used to evaluate the effect of STAT3 in vitro under different matrix stiffnesses. Furthermore, a BALB/c nude mouse model was established to assess the relationship in vivo. Our results confirmed the differential expression of STAT3/p-STAT3 not only in normal and malignant ovarian tissues but also under different matrix stiffnesses. Furthermore, we verified that STAT3 was a mechanically responsive gene both in vitro and in vivo, and the mechanical response was carried out by altering the migration-related molecules (TNFAIP1) and adhesion-related molecules (LPXN, CNN3). The novel findings suggest that STAT3, a potential therapeutic target for clinical diagnosis and treatment, is a mechanically responsive gene that responds to matrix stiffness, particularly regulation in migration and adhesion in the progression of ovarian cancer.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

EOC:

Epithelial ovarian cancer

KDST3:

Knockdown of STAT3

FBS:

Fetal bovine serum

PA gels:

Polyacrylamide gels

FCM:

Flow cytometry

TEM:

Transmission electron microscope

GFP:

Green fluorescent protein

Cytc:

Cytochrome C

MMP2:

Matrix metalloproteinases 2

LOX:

Lysyl oxidase

VEGF:

Vascular endothelial growth factor

HIF-1α:

Hypoxia-inducible factor-1α

IL-6:

Interleukin-6

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Acknowledgements

We thank the lab members for their in-depth discussions and careful reading of this manuscript.

Funding

The present study was supported by Youth Innovation Team of Shandong Province (2022KJ261), the Natural Science Foundation of Shandong Province (grant No. ZR2023MH193, ZR2019MH047, ZR2015HL057), and the National Natural Science Foundation of China (Grant number 81501683).

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Authors and Affiliations

  1. School of Life Science and Technology, Shandong Second Medical University, Weifang, 261053, Shandong, People’s Republic of China

    Sun Chenchen, Qian Xueqian, Lu Yahui, Yuan Yi, Zhang Hui & Han Yangyang

  2. School of Basic Medicine Sciences, Shandong Second Medical University, Weifang, 261053, Shandong, People’s Republic of China

    Bai Lanning

  3. Department of Physiology, Shandong Second Medical University, Weifang, 261053, Shandong, People’s Republic of China

    Cheng Min

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  1. Sun Chenchen
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Contributions

Sun Chenchen performed the experiments and wrote the materials and results section. Zhang Hui and Bai Lanning helped Sun Chenchen finished some of experiments. Lu Yahui, Qian Xueqian, and Yuan Yi analyzed some of the data, and Qian Xueqian also made some revisions in the revised manuscript. Cheng Min provided the experimental instruments. Han Yang-yang designed all of the experiments and wrote the introduction and discussion section.

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Correspondence to Han Yangyang.

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Chenchen, S., Xueqian, Q., Yahui, L. et al. STAT3 mediates ECM stiffness-dependent progression in ovarian cancer. Mol Cell Biochem (2024). https://doi.org/10.1007/s11010-024-04991-5

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