Abstract
BECN1 is a critical regulator of autophagy, which plays important roles in tumor formation and metastasis. However, the autophagy-independent role of BECN1 and the clinical prediction value of BECN1 still need to be explored. Here, we observed significantly lower expression of BECN1 in colorectal cancers (CRCs) compared with adjacent normal colon tissue, and downregulation of BECN1 was positively related to poor prognosis in CRC patients. In addition, we found that knockdown of BECN1 markedly promoted CRC cell motility and invasion. Bioinformatics gene set enrichment analysis (GSEA) revealed that low levels of BECN1 were significantly correlated with the STAT3 signaling pathway in CRC. Consistently, knockdown of BECN1 increased the phosphorylation of STAT3 and activated the STAT3 signaling pathway in CRC cells. Furthermore, we demonstrated that STAT3 was involved in the CRC metastasis mediated by knockdown of BECN1 in vitro and in vivo. Mechanistically, knockdown of BECN1 promoted the phosphorylation of STAT3 via regulation of the interaction between STAT and JAK2 but did not inhibit autophagy. Our study revealed that BECN1 served as a negative regulator of CRC metastasis by regulating STAT3 signaling pathway activation in an autophagy-independent manner. The BECN1/JAK2/STAT3 signaling pathway can be used as a potential therapeutic target for metastatic CRC.
Highlights
BECN1, which contains a Bcl-2 homology (BH3)domain, a coiled-coil domain (CCD) and an evolutionarily conserved domain (ECD), has been identified as an important autophagy effector and plays a critical role in autophagy[1]
Consistent with the above results, the TCGA colorectal cancer RNAseq database results indicated BECN1 downregulation in human colorectal cancers (CRCs) tissues (Fig. S1A). To further confirm these public database results, we examined the expression of BECN1 in human CRC tissues and showed that BECN1 was significantly downregulated in 12 CRC patient tissues compared with the paired adjacent normal tissues (Fig. 1b, c)
By analyzing two different CRC GEO databases, we found that lower mRNA levels of BECN1 were associated with poorer disease-free survival (DFS) and recurrence-free survival (RFS) in CRC (Fig. 1f, g)
Summary
BECN1, which contains a Bcl-2 homology (BH3)domain, a coiled-coil domain (CCD) and an evolutionarily conserved domain (ECD), has been identified as an important autophagy effector and plays a critical role in autophagy[1]. BECN1 interacts with Vps[34] and other factors to regulate autophagosome formation[2,3,4]. BECN1 was reported to bind to Bcl family proteins, such as Bcl-2 and Bcl-XL, which in turn counteracted the effect of BECN1 on autophagy[5,6,7]. Autophagy is a survival-promoting pathway that captures, degrades, and. Loss of BECN1 promotes mammary tumor development via regulation of WNT113, while it has been demonstrated that BECN1 is essential for the tumorigenesis of breast cancer progenitor cells[14]. Previous reports have shown that heterozygous disruption of the BECN1 autophagy gene increases spontaneous tumorigenesis[15]. High expression of Beclin-1 predicted a good overall survival rate in non-Hodgkin’s lymphomas[17], suggesting that BECN1 is a tumor suppressor.
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