Cancer-associated Fibroblast-derived Extracellular Vesicles Promote Lymph Node Metastases in Oral Cavity Squamous Cell Carcinoma by Encapsulating ITGB1 and BMI1

Overview

Journal BMC Cancer

Publisher Biomed Central

Specialty Oncology

Date 2024 Jan 23

PMID 38254031

Authors

Tianzhu Lv

Hongjing Liu

Ling Mao

Yanrong Song

Lili Liao

Kun Zhong

Binbin Shuai

Yingkun Luo

Tingting Guo

Wentao Huang

Shenyingjie Zhang

Affiliations

Soon will be listed here.

Abstract

Background: Extracellular vesicles (EVs) have been revealed to facilitate the development of oral squamous cavity cell carcinoma (OCSCC), while its supporting role in lymph node metastases is under continuous investigation. This study aimed to examine the function of cancer-associated fibroblasts (CAF)-derived EVs (CAF-EVs) during lymph node metastasis in OCSCC and the mechanisms.

Methods: CAF were isolated from OCSCC tissues of patients, and CAF-EVs were extracted and identified. EdU, colony formation, wound healing, and Transwell assays were performed. The OCSCC cells before and after CAF-EVs treatment were injected into mice to probe the effects of CAF-EVs on tumor growth and lymph node metastasis, respectively. The effect of CAF-EVs treatment on transcriptome changes in OCSCC cells was analyzed. Clinical data of patients with OCSCC were analyzed to determine the prognostic significance of the selected genes. Finally, loss-of-function assays were conducted to corroborate the involvement of polycomb complex protein BMI-1 (BMI1) and integrin beta1 (ITGB1).

Results: CAF-EVs promoted the malignant behavior of OCSCC cells and accelerated tumor growth and lymph node metastasis in mice. CAF-EVs significantly increased the expression of BMI1 and ITGB1, and the expression of BMI1 and ITGB1 was negatively correlated with the overall survival and relapse-free survival of OCSCC patients. Knockdown of BMI1 or ITGB1 in OCSCC cells abated the promoting effects of CAF-EVs in vitro and in vivo.

Conclusion: CAF-EVs elicited the metastasis-promoting properties in OCSCC by elevating BMI1 and ITGB1, suggesting that BMI1 and ITGB1 could be potential biomarkers and therapeutic targets for OCSCC.

Citing Articles

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References

Kurihara K, Isobe T, Yamamoto G, Tanaka Y, Katakura A, Tachikawa T . Expression of BMI1 and ZEB1 in epithelial-mesenchymal transition of tongue squamous cell carcinoma. Oncol Rep. 2015; 34(2):771-8. DOI: 10.3892/or.2015.4032. View

Sun R, Yuan L, Jiang Y, Wan Y, Ma X, Yang J . ALKBH5 activates FAK signaling through m6A demethylation in mRNA and enhances tumor-associated lymphangiogenesis and lymph node metastasis in ovarian cancer. Theranostics. 2023; 13(2):833-848. PMC: 9830429. DOI: 10.7150/thno.77441. View

Dourado M, Korvala J, Astrom P, de Oliveira C, Cervigne N, Mofatto L . Extracellular vesicles derived from cancer-associated fibroblasts induce the migration and invasion of oral squamous cell carcinoma. J Extracell Vesicles. 2019; 8(1):1578525. PMC: 6374932. DOI: 10.1080/20013078.2019.1578525. View

Shoucair I, Mello F, Jabalee J, Maleki S, Garnis C . The Role of Cancer-Associated Fibroblasts and Extracellular Vesicles in Tumorigenesis. Int J Mol Sci. 2020; 21(18). PMC: 7555043. DOI: 10.3390/ijms21186837. View

Takahara T, Kasamatsu A, Yamatoji M, Iyoda M, Kasama H, Saito T . SIPA1 promotes invasion and migration in human oral squamous cell carcinoma by ITGB1 and MMP7. Exp Cell Res. 2017; 352(2):357-363. DOI: 10.1016/j.yexcr.2017.02.026. View

Sun L, Xu K, Cui J, Yuan D, Zou B, Li J . Cancer‑associated fibroblast‑derived exosomal miR‑382‑5p promotes the migration and invasion of oral squamous cell carcinoma. Oncol Rep. 2019; 42(4):1319-1328. PMC: 6718099. DOI: 10.3892/or.2019.7255. View

Dourado M, Guerra E, Salo T, Lambert D, Coletta R . Prognostic value of the immunohistochemical detection of cancer-associated fibroblasts in oral cancer: A systematic review and meta-analysis. J Oral Pathol Med. 2017; 47(5):443-453. DOI: 10.1111/jop.12623. View

Naito Y, Yoshioka Y, Ochiya T . Intercellular crosstalk between cancer cells and cancer-associated fibroblasts via extracellular vesicles. Cancer Cell Int. 2022; 22(1):367. PMC: 9686122. DOI: 10.1186/s12935-022-02784-8. View

Zhang X, Wang Y, Wang X, Zou B, Mei J, Peng X . Extracellular vesicles-encapsulated microRNA-10a-5p shed from cancer-associated fibroblast facilitates cervical squamous cell carcinoma cell angiogenesis and tumorigenicity via Hedgehog signaling pathway. Cancer Gene Ther. 2020; 28(5):529-542. DOI: 10.1038/s41417-020-00238-9. View

10.

Zhang Y, Liu J, Liu S, Yu L, Liu S, Li M . Extracellular vesicles in oral squamous cell carcinoma: current progress and future prospect. Front Bioeng Biotechnol. 2023; 11:1149662. PMC: 10250623. DOI: 10.3389/fbioe.2023.1149662. View

11.

Zhao Y, Yang W, Zheng K, Chen J, Jin X . The role of BMI1 in endometrial cancer and other cancers. Gene. 2022; 856:147129. DOI: 10.1016/j.gene.2022.147129. View

12.

Gu W, Sun H, Zhang M, Mo S, Tan C, Ni S . ITGB1 as a prognostic biomarker correlated with immune suppression in gastric cancer. Cancer Med. 2022; 12(2):1520-1531. PMC: 9883581. DOI: 10.1002/cam4.5042. View

13.

Chen C, Yang C, Tian X, Liang Y, Wang S, Wang X . Downregulation of miR-100-5p in cancer-associated fibroblast-derived exosomes facilitates lymphangiogenesis in esophageal squamous cell carcinoma. Cancer Med. 2023; 12(13):14468-14483. PMC: 10358253. DOI: 10.1002/cam4.6078. View

14.

Li Z, Wang Y, Yuan C, Zhu Y, Qiu J, Zhang W . Oncogenic roles of Bmi1 and its therapeutic inhibition by histone deacetylase inhibitor in tongue cancer. Lab Invest. 2014; 94(12):1431-45. DOI: 10.1038/labinvest.2014.123. View

15.

Li Y, Tao Y, Gao S, Li P, Zheng J, Zhang S . Cancer-associated fibroblasts contribute to oral cancer cells proliferation and metastasis via exosome-mediated paracrine miR-34a-5p. EBioMedicine. 2018; 36:209-220. PMC: 6197737. DOI: 10.1016/j.ebiom.2018.09.006. View

16.

Liu Z, Hu C, Zheng L, Liu J, Li K, Li X . BMI1 promotes cholangiocarcinoma progression and correlates with antitumor immunity in an exosome-dependent manner. Cell Mol Life Sci. 2022; 79(9):469. PMC: 11071914. DOI: 10.1007/s00018-022-04500-1. View

17.

Chamoli A, Gosavi A, Shirwadkar U, Wangdale K, Behera S, Kurrey N . Overview of oral cavity squamous cell carcinoma: Risk factors, mechanisms, and diagnostics. Oral Oncol. 2021; 121:105451. DOI: 10.1016/j.oraloncology.2021.105451. View

18.

Urabe F, Kosaka N, Ito K, Kimura T, Egawa S, Ochiya T . Extracellular vesicles as biomarkers and therapeutic targets for cancer. Am J Physiol Cell Physiol. 2019; 318(1):C29-C39. DOI: 10.1152/ajpcell.00280.2019. View

19.

Kim S, Woo S, Noh J, Lee M, Lee Y, Lee J . Association between cancer stem cell gene expression signatures and prognosis in head and neck squamous cell carcinoma. BMC Cancer. 2022; 22(1):1077. PMC: 9583594. DOI: 10.1186/s12885-022-10184-4. View

20.

Chernova T, Grosso S, Sun X, Tenor A, Cabeza J, Craxton A . Extracellular Vesicles Isolated from Malignant Mesothelioma Cancer-Associated Fibroblasts Induce Pro-Oncogenic Changes in Healthy Mesothelial Cells. Int J Mol Sci. 2022; 23(20). PMC: 9604431. DOI: 10.3390/ijms232012469. View