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)