Fusobacterium nucleatum Promotes Colorectal Cancer Metastasis by Modulating KRT7-AS/KRT7

Abstract

Background: The enrichment of Fusobacterium nucleatum (Fn) has been identified in CRC patients and associated with worse outcomes. However, whether Fn was involved in the metastasis of CRC was not well determined. Methods: CRC cell lines were incubated with Fn and the migration ability was analyzed by transwell and would healing assays. Fn-treated or untreated CRC cells were intravenously injected into nude mice to evaluate the lung metastasis. Fluorescence in situ hybridization was performed to detect the colonization of Fn. RNA sequencing and validation studies were performed to identify the mechanism by which Fn promote CRC metastasis. Findings::The abundance of Fn was significantly increased in CRC patients with lymph nodes metastasis.Fn infection promoted CRC cells migration in vitro, as well as lung metastasis in vivo. Colonization of Fn was detected in metastatic lung lesions of nude mice. RNA sequencing revealed that Fn significantly upregulated the expression of long non-coding RNA Keratin7-antisense (KRT7-AS) and Keratin7 (KRT7) in CRC cells. Fn-induced CRC lung metastasis was attenuated by the depletion of KRT7-AS. In addition, KRT7-AS facilitated CRC cells migration by upregulating KRT7. Fn upregulated KRT7-AS by activating NF-κB signaling pathway. Importantly, the expression of KRT7-AS was positively correlated with the abundance of Fn in CRC tissues. Interpretation: Fn infection activated NF-κB pathway, leading to increased expression of KRT7-AS/KRT7, which promoted CRC cell migration in vitro and metastasis in vivo. Funding Statement: This work was supported by National Key R&D Program of China(2016YFC0107003 and 2016YFC1303200) , the National Natural Science Foundation of China (81702308). Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: All animal procedures were performed in compliance with ethical standards and approved by the Animal Care Committee of Zhejiang University.