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Page 10 of 20 Vidoni et al. J Cancer Metastasis Treat 2021;7:4 I http://dx.doi.org/10.20517/2394-4722.2020.95

Both miRNAs and lncRNAs can be found in the tumor microenvironment [80,82] . CAFs can transfer their
ncRNAs to the tumor microenvironment via exosome release [83-85] . In the context of cancers affecting
women, it is reported that three miRNAs, namely miR-21, miR-378e, and miR-143, were increased in
exosomes from CAFs as compared to those from normal fibroblasts, and these miRNAs when transferred
[85]
to breast cancer cells increased their aggressiveness .

The clinical implication of dysregulated autophagy in cancers affecting women has been reported in several
studies, both in vitro and in vivo, as well as in tumor-bearing patients. For instance, in breast cancer it has
[5-7]
been shown that autophagy inhibition enhances tumor sensitivity to therapeutic agents . Accordingly,
in paclitaxel-resistant triple-negative breast cancer cells, cell death ensued upon down-regulating
[86]
autophagy . Accordingly, reduced level of BECLIN1 and LC3 expression correlated with better endocrine
therapy response in hormone-responsive breast cancer . In other studies, the sensitivity to anti-hormone-
[87]
and chemo-therapies in breast cancer ameliorated following autophagy inhibition with chloroquine and
3-methyladenine treatments, respectively [88,89] . Similarly, chloroquine inhibition of autophagy degradation
[90]
could avoid carboplatin resistance and ovarian tumor recurrence . At variance, it has been shown
that in ovarian cancer the low expression of BECLIN1 was a negative prognostic factor to platinum-
[91]
based chemotherapy response , whereas the up-regulation of BNIP3, a positive regulator of mitophagy,
potentiated cisplatin-sensitivity .
[92]
Down-regulation of autophagy has been reported in HPV-positive cervical cancers following EGFR-
[93]
mediated activation of the AKT/mTOR pathway . Additionally, the HPV oncoproteins E5, E6, and E7
have been shown to interfere with the autophagic machinery at different steps, either by reducing the
[10]
expression of key regulators and ATG genes or by impairing the autophagosome-lysosome fusion . These
studies highlight the dual role of autophagy dysregulation in cancer development and in the therapeutic
outcome, which might be explained by different genetic and epigenetic alterations in cancer cells that
differently impact on the response to tumor microenvironment stimuli.

Non-coding RNAs regulation of autophagy in cancers affecting women
As outlined above, the role of autophagy in cancer progression is strictly dependent on genetic and
epigenetic events that impinge on the integrity of the autophagic machinery and of its regulatory pathways
[Figure 7].

During cancer evolution, these events become more frequent, adding to the clonal heterogeneity that
characterizes the progression phase. Changes in the tumor microenvironment and the therapeutic
treatments further increase the occurrence of genetic lesions as well as of epigenetic modulation of the
genes that shape cancer cell phenotype.

Here, we schematically summarize the current knowledge on the epigenetic modulation of autophagy in
female malignant tumors, with a focus on non-coding RNAs acting either on ATGs and on their regulators.
The miRNAs and lncRNAs and their molecular targets involved in the autophagy pathway are reported in
Tables 1 and 2, respectively. An ample set of miRNAs with either oncogenic or tumor suppressive function
have been shown to affect the regulation of autophagy in cancers affecting women (reviewed in [94,95] ).

For instance, low expression of miR-29b and, consequently, high expression of its target ATG9, has been
[96]
associated with ovarian cancer relapse . In ovarian cancer, miR-34 is expressed at low levels, while its
over-expression suppressed the NOTCH signaling pathway resulting in upregulation of autophagy and
[97]
induction of apoptosis thus limiting cancer aggressiveness . At variance, in cervical cancer, high levels
of miR-34C-5p down-regulated autophagy, thus improving the chemotherapy response, by targeting
[98]
ATG4B . In cervical cancer, miR-7-5p promotes autophagy by targeting BCL-2 thus freeing BECLIN-1,
[99]
and this results in chemoresistance to cisplatin .