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 β4, 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 β4 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 β4 expression was significantly upregulated in the tumors with infiltrating growth pattern, as well as those with positive lymphovascular invasion. Moreover, β4 was invariably overexpressed in the lymphovascular tumor thrombi, which has not been reported before. After shRNA-induced knockdown of β4 in vitro, the migration, invasion and scratch repair ability of the tumor cells were significantly reduced. Furthermore, β4 reduction decreased anchorage-independent growth and increased anoikis. The bioinformatics analysis revealed that approximately 70 pathways were significantly dysregulated in the high β4 expression group. The MAPK pathway and propanoate metabolism were located in the network center of those pathways. Taken together, our results suggest that β4 could promote the tumor's aggressiveness by enhancing invasion and antagonizing anoikis. The upregulated expression of β4 in the tumor thrombi is intrinsically linked to its role in strengthening the anoikis resistance.