TFEB and autophagy in endometriosis
Endometriosis is characterized by the implantation of endometrial glands and stroma deep into the outside of the uterine cavity.(3) It mainly involves the ovaries and adjacent pelvic peritoneum. Endometriosis is not malignant, but its ability to infiltrate and invade distant tissues follows the same pattern as metastases from malignant tumors. As a chronic and estrogen-dependent disease, there are many theories about the pathogenesis of endometriosis, but no one can fully explain it. Autophagy has been a hot topic in recent years. It has also been reported to affect the production and invasion of ectopic endometrial tissues from endometriosis patients.(34) TFEB is a key factor in the formation of autophagic lysosomes. Roland P. Kuiper et al’s study showed that TFEB was expressed in the endometrium, although its highest expression was in the placenta and lung.(35) Therefore, TFEB may play a role in the development of endometriosis. However, there are no reports about TFEB and endometriosis at home and abroad.
1.autophagy in Endometriosis is down-regulated through the TFEB-mediated mTOR dependent pathway
Many studies have shown that autophagy is down-regulated in endometriosis by detecting autophagy-related molecules and proteins. It is well known that inhibition of mTOR can activate autophagy, and the PI3K/AKT pathway is considered to be a positive regulator of mTOR activity.(36) Meanwhile, PI3K/AKT/mTOR pathway is a classic signaling pathway regulating autophagy. The PI3K/AKT/mTOR signaling pathway has been found to be closely related to endometriosis. Phosphorylation of various proteins in the PI3K/AKT/mTOR pathway leads to molecular interactions and ultimately the formation of endometriosis.(37) Guo J et al discovered that the phosphorylation level of mTOR in ectopic endometrium in patients with endometriosis was higher than that in eutopic endometrium.(38) Besides, inhibition of mTOR can alleviate the development of endometritis foci in rat/mouse models of endometriosis.(39) Moreover, in the mouse model established by Yan Liu et al, the inhibition of the PI3K/AKT/mTOR signaling pathway can alleviate endometriosis-associated sciatic nerve pain in a rat model of sciatic endometriosis,(40) Zhang L et al’s study revealed that Beclin-1 mRNA and protein expression in eutopic and ectopic endometrium of patients with endometriosis was significantly reduced. Lei Zhan et al. studied autophagy marker proteins LC3 and P62 in the endometrium of endometriosis and leiomyoma. They found compared with the endometrium of leiomyoma group in the ectopic and eutopic endometrium of endometriosis groups, the expression of P62 was significantly higher. In comparison, the expressions of LC3 were down-regulated.(41) LC3 is proved as a credible marker of the autophagosome in mammalian cells. After the formation of autophagosome, LC3-I was subsequently combined with phospholipid-ethanolamine (PE) to form LC3-II, which was bound to the inner and outer membrane of autophagosome. Through binding directly to LC3, P62 /SQSTM1 selectively binds to autophagosomes and is effectively degraded by autophagy, therefore, the expression level of P62 was negatively correlated with autophagy activity.(42) All of these studies have revealed inadequate levels of autophagy in endometriosis. But the exact mechanism, however, is unclear. TFEB is a key factor in the formation of autophagic lysosomes. mTOR is the upstream signal molecule of TFEB, LC3II and p62 are the marker proteins after the autophagic lysosomes formation. Therefore, TFEB may play role in endometriosis tissue. The activated mTOR may phosphorylate the serine residues of TFEB and locate TFEB in the cytoplasm, thus preventing the formation of autophagic lysosome and cannot clearing the ectopic endometrium. In addition, Liang et al. found that there was a positive association between the expression of Beclin1 and TFEB, whereas TFEB silencing suppressed Beclin1 amplification. So the Low beclin-1 mRNA and protein expression in ectopic endometrium in patients with endometriosis may be caused by down-regulation of TFEB.(43)