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Figure 7. Dual role of autophagy in cancer progression. Involvement of epigenetic mechanism on autophagy affects the bidirectional
impact of autophagy process on cancer growth and, thus, onto the onset of metastasis, leading to cancer relapse. : impact on;→:
activation; ⊥: inhibition

The most relevant miRNAs that modulate autophagy are shown in Table 1, and include miR-30d, miR30a,
miR-376b, miR-21, and miR-20a among others. Low expression of BECLIN 1, a well-known haplo-
insufficient tumor suppressor, is associated with increased women’s cancer development and reduced
chemotherapy response [100-102] . Both in ovarian and breast cancers, BECLIN 1 has been shown to be
[95]
post-transcriptionally downregulated by several miRNAs, including miR-30a [103] , and miR30d , miR-
376b [104] , and miR-20a [105] . MiR-30d is an oncomiRNA known to regulate several cellular processes,
including apoptosis, senescence, proliferation, and differentiation [106] . This oncomiRNA has been shown
to suppress autophagy in human ovarian and breast cancer cells by negatively affecting the expression of
[95]
ATG2, ATG5, ATG12, and BNIP3, besides BECLIN 1 . DIRAS3 (also known as ARH-I), a well-known
tumor suppressor genetically imprinted in ovarian cancer, is a positive interactor of BECLIN 1 involved in
autophagy-dependent induction of cancer cell dormancy [107] and inhibition of cancer cell migration [108] . In
ovarian cancer cells, DIRAS3 expression is epigenetically repressed by several predicted miRNAs, such as
miR-1305, miR-1260a, miR-141-3p, miR-424-5p, miR-15a-5p, and miR-7-5p [109] . Interestingly, in ovarian
cancer cells the pro-inflammatory cytokine IL-6 induces the expression of these miRNAs resulting in
inhibition of DIRAS3-BECLIN 1-dependent autophagy and consequent stimulation of cell migration [109] .
Besides targeting BECLIN 1, miR20a also targets ATG16 in breast cancer [107] , while miR376b also targets
ATG4 in breast cancer [105] . Let-7a is a tumor suppressor miRNA known to down-regulate the RAS
oncogenic pathway in a variety of cancers, and its high expression correlates with chemo-responsiveness,
low invasiveness, and better survival in ovarian cancer patients [110,111] . In ovarian cancer, this miRNA was
shown to prevent the formation of autophagosomes by targeting ATG4 (the LC3 processing enzyme),
[94]
ATG9A, and ATG16L . Interestingly, autophagy degradation of p62/SQSTM1 led to decreased levels of
the miRNA-processing enzyme DICER1 resulting in increased miR-Let-7a and suppression of ovarian
cancer motility [112] .

The dual lipid-protein phosphatase PTEN is a well-known tumor suppressor, and its deletion or silencing
concurs to maintain the PI3KC1-AKT-mTORC1 pathway active, which results in down-regulation of
autophagy [113-115] . In breast, ovarian, and cervical cancer, PTEN was found post-transcriptionally silenced by
the oncogenic miR-21, whose high expression correlated with tumorigenesis, metastasis, and poor clinical
[94]
outcome [116-118] . In ovarian cancer, both Let-7a and miR-21 were shown to target TSC1 , an inhibitor of
mTORC1.