Giant obscurin regulates migration and metastasis via RhoA-dependent cytoskeletal remodeling in pancreatic cancer
| Autor: | Bin Sheng Wong, Soontorn Tuntithavornwat, Se Jong Lee, Daniel J. Shea, Lei Zheng, Talia Guardia, Christopher L. Yankaskas, Konstantinos Konstantopoulos, Aikaterini Kontrogianni-Konstantopoulos |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
RHOA Mice SCID Protein Serine-Threonine Kinases medicine.disease_cause Article Metastasis Focal adhesion Mice Cell Movement Mice Inbred NOD Pancreatic cancer Cell Line Tumor medicine Animals Humans Neoplasm Metastasis Cytoskeleton biology Cancer Cell migration medicine.disease Pancreatic Neoplasms Oncology biology.protein Cancer research Heterografts Female Carcinogenesis rhoA GTP-Binding Protein Rho Guanine Nucleotide Exchange Factors |
| Zdroj: | Cancer Lett |
| Popis: | Obscurins, encoded by the OBSCN gene, are giant cytoskeletal proteins with structural and regulatory roles. Large scale omics analyses reveal that OBSCN is highly mutated across different types of cancer, exhibiting a 5-8% mutation frequency in pancreatic cancer. Yet, the functional role of OBSCN in pancreatic cancer progression and metastasis has to be delineated. We herein show that giant obscurins are highly expressed in normal pancreatic tissues, but their levels are markedly reduced in pancreatic ductal adenocarcinomas. Silencing of giant obscurins in non-tumorigenic Human Pancreatic Ductal Epithelial (HPDE) cells and obscurin-expressing Panc5.04 pancreatic cancer cells induces an elongated, spindle-like morphology and faster cell migration via cytoskeletal remodeling. Specifically, depletion of giant obscurins downregulates RhoA activity, which in turn results in reduced focal adhesion density, increased microtubule growth rate and faster actin dynamics. Although OBSCN knockdown is not sufficient to induce de novo tumorigenesis, it potentiates tumor growth in a subcutaneous implantation model and exacerbates metastasis in a hemispleen murine model of pancreatic cancer metastasis, thereby shortening survival. Collectively, these findings reveal a critical role of giant obscurins as tumor suppressors in normal pancreatic epithelium whose loss of function induces RhoA-dependent cytoskeletal remodeling, and promotes cell migration, tumor growth and metastasis. |
| Databáze: | OpenAIRE |
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