Abstract
MRE11, the nuclease component of RAD50/MRE11/NBS1 DNA repair complex which is essential for repair of DNA double-strand-breaks in normal cells, has recently garnered attention as a critical factor in solid tumor development. Herein we report the crucial role of MRE11 in oral cancer progression in a nuclease-independent manner and delineate its key downstream effectors including CXCR4. MRE11 expression in oral cancer samples was positively associated with tumor size, cancer stage and lymph node metastasis, and was predictive of poorer patient survival and radiotherapy resistance. MRE11 promoted cell proliferation/migration/invasion in a nuclease-independent manner but enhanced radioresistance via a nuclease-dependent pathway. The nuclease independent promotion of EMT and metastasis was mediated by RUNX2, CXCR4, AKT, and FOXA2, while CXCR4 neutralizing antibody mitigated these effects in vitro and in vivo. Collectively, MRE11 may serve as a crucial prognostic factor and therapeutic target in oral cancer, displaying dual nuclease dependent and independent roles that permit separate targeting of tumor vulnerabilities in oral cancer treatment.
Highlights
Oral squamous cell carcinoma (OSCC) is the 6th most common cancer worldwide [1], and it is prevalent in Southeast Asian countries, with Taiwan reporting the highest global incidence [2, 3]
The clastogenic effect of ionizing radiation (IR) and chemotherapy is impaired in high MRE11 expressing phenotypes of breast and lung cancers, with recent data suggesting that high MRE11 expression lung cancer phenotypes may be protected from endogenous tumor related replication stress [11]
To confirm whether expression of MRE11 protein was elevated in oral cancer tissues, immunohistochemical analysis was performed and the results showed that MRE11 expression is relatively low in normal oral epithelium compared to its expression level in oral cancer tissues (Fig. 1 D and E) (p = 0.0017)
Summary
Oral squamous cell carcinoma (OSCC) is the 6th most common cancer worldwide [1], and it is prevalent in Southeast Asian countries, with Taiwan reporting the highest global incidence [2, 3]. MRE11 is essential for protection of genomic stability, with nuclease activity of MRE11 shown to facilitate protection against oncogene induced replication stress in B lymphocytes [10], it may likewise exhibit maladaptive effects in the protection of established tumors from exogenous and endogenous sources of DNA damage. There are conflicting data regarding the role of MRE11 in carcinogenesis, with other studies finding that MRE11 may inhibit rather than promote oncogene driven tumorigenesis and metastasis [13]. This may reflect its complex and incompletely understood role in both protection of normal cell phenotypes from genomic instability, and the facilitation of cancer cell survival in the face of exogenous and endogenous DNA damage
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