Oral squamous cell carcinoma (OSCC) is one of the most deadly malignant tumors with high invasive potential and frequently cervical lymph node metastasis. AP‐1 plays a critical role in tumor invasion and metastasis, but there are few reports on the role of c‐Fos in OSCC carcinogenesis and metastasis.

Investigate c‐Fos expression in clinical samples from 58 primary patients with OSCC by immunohistochemistry. c‐Fos knockdown stable cell lines were established by lentiviral infection and transwell cell invasion assay to detect the effects of c‐Fos knockdown on tumor cell invasion.

Nuclear and cytoplasmic c‐Fos protein were both overexpression in cancerous tissues compared with adjacent non‐malignant epithelia (nuclear: P < 0.001, cytoplasmic: P = 0.005). Higher level nuclear c‐Fos expression was found in the tumor samples of patients with lymph node metastasis than those without lymph node metastasis (4.85 ± 1.43 vs. 3.61 ± 1.28, P = 0.002). Higher level of c‐Fos expression was also found in tumor invasive front margin than tumor center and high nuclear expression of c‐Fos indicated poor survival. Knockdown of c‐Fos greatly suppressed tumor cell proliferation and invasion and downregulated CD44 and CyclinD1 expression in HN6 and SCC9 cells. However, CyclinD3, c‐myc, and Erk1/2 were found no changes to c‐Fos depletion.

c‐Fos promoted cell invasion and migration via CD44 pathway in OSCC. c‐Fos could be used as a potential therapeutic target gene and an additional marker for evaluation of lymph node metastasis.