Hypoxia-induced MFAP5 Promotes Tumor Migration and Invasion via AKT Pathway in Head and Neck Squamous Cell Carcinoma

Abstract

Objective: Microfibrillar-associated protein 5 (MFAP5) is highly expressed in many types of cancers. Our previous study has observed that overexpression of MFAP5 was correlated with lymph nodes metastasis and poor prognosis in head and neck squamous cell carcinoma (HNSCC), but the underlying mechanism is poorly understood. Materials and methods: The MFAP5 expression is detected under hypoxia condition. HNSCC cell lines are transfected with MFAP5-expressing lentivirus vector to establish stable overexpression model. Wound-healing, migration and invasion assay are used to determine the effect of MFAP5 on HNSCC and metastasis-related proteins are examined by Western blot. In vivo lung metastasis assays are conducted by the tail vein injection. In addition, immunohistochemistry is applied to analyze the correlation of MFAP5, hypoxia-induced factor-1 α (HIF-1α), and vimentin in 84 HNSCC patients' tissue samples. Results: Firstly, MFAP5 expression can be markedly induced under hypoxia condition in HNSCC cell lines. Cell lines with MFAP5 overexpression has a significant higher ability of migration and invasion. In addition, in vivo assay observes that overexpression of MFAP5 can promote tumor lung metastasis. Furthermore, MFAP5 facilitates this process by activating epithelial-mesenchymal transition (EMT) program via AKT pathway in HNSCC cell lines. The pro-metastatic effect of MFAP5 can be reversed by MK2206, an AKT phosphorylation inhibitor. Lastly, the positive correlation among HIF-1α, MFAP5 and vimentin from tissue samples and TCGA dataset are also observed in HNSCC. Conclusion:Our study demonstrates MFAP5 plays a critical role in hypoxia-induced EMT program via AKT pathway in HNSCC, which would be a very promising therapeutic target.

The genomic response of human granulosa cells (KGN) to melatonin and specific agonists/antagonists to the melatonin receptors

“…The Akt pathway is downstream of some of these regulators such as MFAP5, PDZK1, and CAV1, which are related to cell progression and growth. The expression of MFAP5 also affected inflammatory related genes in previous studies 31,33,35 , and its inhibition in our data by NAS suggests that MT1 may be responsible for limiting GC proliferation and growth, and at the same time preventing early luteinization at the antral follicular stage through activation of the Akt pathway.…”

“…The list of upstream regulators identified in response to the MT1 agonist N-acetyl serotonin (NAS) used in combination with melatonin (10 −9 M) is available in Supplemental table 7. Microfibrillar-Associated Protein 5 (MFAP5), which is downstream of Akt, downregulates inflammation and controls cell proliferation and progression, had a tendency to be inhibited [31][32][33] . Another factor downstream of Akt, PDZ Domain Containing 1 (PDZK1), also known as Na + /H + Exchanger Regulator Factor-3 (NHERF3) was identified as an upstream regulator.…”

Identification of a Hypoxia-Related lncRNA Biomarker Signature for Head and Neck Squamous Cell Carcinoma

“…Hypoxia, a frequent condition in HNSCC, has been reported to be a critical component of malignant behavior and treatment resistance [ 42 ]. Xu et al demonstrated that MFAP5 could boost EMT process by activation of AKT under hypoxia status [ 43 ]. After hypoxia treatment in HNSCC cell lines, the expression of SRGN was increased by secretion of cancer-associated fibroblasts, which in turn stimulates tumor exacerbation via Wnt/ β -catenin axis [ 44 ].…”

Establishment and Analysis of Hypoxia-Related Model in Oral Squamous Cell Carcinoma

“…In addition, in vivo analysis showed that overexpression of MFAP5 could promote tumor lung metastasis. Experiments show that MFAP5 may promote this process by activating epithelial mesenchymal transformation (EMT) through Akt pathway [ 7 ]. In addition, studies have found that hypoxia-induced ZEB1 can promote the progression of cervical cancer through CCL8-dependent recruitment of tumor-associated macrophages [ 8 ].…”