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.