Integrin β4 promotes invasion and anoikis resistance of papillary thyroid carcinoma and is consistently overexpressed in lymphovascular tumor thrombus

Although the majority of papillary thyroid cancers (PTC) are indolent, a subset of PTCs behaves aggressively due to extensive invasion and distant metastasis. Integrin beta 4, a member of the integrin family, has been shown to enhance the progression in some malignancies; however, its role in PTC remains unclear. Here, we demonstrated that beta 4 overexpression was associated with extrathyroid extension, lymph node metastasis, high TNM stage, and poor overall survival based on The Cancer Genome Atlas cohort. Immunohistochemistry showed that beta 4 expression was significantly upregulated in the tumors with infiltrating growth pattern, as well as those with positive lymphovascular invasion. Moreover, beta 4 was invariably overexpressed in the lymphovascular tumor thrombi, which has not been reported before. After shRNA-induced knockdown of beta 4 in vitro, the migration, invasion and scratch repair ability of the tumor cells were significantly reduced. Furthermore, beta 4 reduction decreased anchorage-independent growth and increased anoikis. The bioinformatics analysis revealed that approximately 70 pathways were significantly dysregulated in the high beta 4 expression group. The MAPK pathway and propanoate metabolism were located in the network center of those pathways. Taken together, our results suggest that beta 4 could promote the tumor's aggressiveness by enhancing invasion and antagonizing anoikis. The upregulated expression of beta 4 in the tumor thrombi is intrinsically linked to its role in strengthening the anoikis resistance.