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Due to their length leading to base pairing, they are facilitated to assembly with DNA, RNA, and proteins,
[61]
creating high-order macromolecular architectures that act as three-dimensional regulatory complexes .
LncRNAs may act both within the nucleus and the cytoplasm and regulate gene expression at both
[62]
transcriptional and post-transcriptional level through different mechanisms . In the nucleus, lncRNAs
can (1) act as scaffold platforms recruiting to the DNA coding region the regulatory proteins complex to
modulate positively or negatively gene expression; or (2) affect the conformation changes of chromosomes
and the spliceosome activity; or (3) act as decoy, repressing gene expression by preventing the interaction
between transcription factors and the promoter; or (4) inhibit the transcription by modifying allosterically
RNA-binding proteins [62,64] . In the cytoplasm, lncRNAs can affect mRNA stability or its translation by acting
[65]
as a sponge of microRNAs .
A novel group of ncRNAs, known as circular RNAs (circRNAs), has been described. CircRNAs are
endogenous single-strand continuous loop structure, made of about 100 nucleotides, that show the 3’ and 5’
[66]
ends covalently linked together . Thanks to the circular conformation that lacks exposed ends, circRNAs
[67]
are highly stable structure very less sensitive to the nuclease degradation . Although their mechanism
of action is still to be clarified, circRNAs may regulate gene expression acting as cytoplasmic microRNA
[68]
sponges or by sequestering RNA-binding proteins or by interfering with DNA transcription .
ROLE AND REGULATION OF AUTOPHAGY IN CANCERS AFFECTING WOMEN
Primitive mutations and epigenetic modulation of oncogenes and of tumor suppressor genes involved
in the autophagy pathway may affect the regulation and the effective role of autophagy during cancer
development and progression. On one side, the autophagic process protects from cellular damage and
[69]
genomic instability thus preventing neoplastic transformation . In this respect, autophagy exerts its
tumor-suppressive role through the elimination of reactive oxygen species, which may cause DNA damages,
and through the degradation of oncogenic and toxic unfolded proteins . On the contrary, autophagy may
[69]
protect cancer cells from DNA and cellular damage induced by therapeutic agents (e.g., radio- and chemo-
therapy) and provide pro-survival resistance to harsh conditions, such as hypoxia, nutrient starvation,
and lack of growth factors [70,71] . In particular, this behavior is typical of cancer cells located in the hypoxic
niche (i.e., the inner part of the tumor mass distant from blood vessels). Thus, in the late stage of cancer
progression, autophagy may turn into a “tumor promoting” process by increasing chemoresistance, by
ensuring the maintenance of cancer stemness and by driving tumor cells in a dormant state, which could
[72]
eventually give rise to relapses and metastasis in distant organs . Cancer progression reflects the dynamic
changes in the permissive tumor microenvironment, in its cellular and molecular composition, as well as
in the heterotypic interactions between tumor and stromal cells. Recent studies support the view that a
“metabolic symbiosis” exists between cancer associated fibroblasts (CAFs) and cancer cells. Such metabolic
crosstalk between stromal and cancer cells reciprocally affects autophagy regulation, which then reflects
in the malignant progression of the cancer with onset of chemoresistance, relapse, and metastasis [9,73-76] .
CAFs can affect autophagy in cancer cells through the release of inflammatory cytokines (e.g., IL-6 and
IL-8) and oncometabolites (e.g., glutamine, lactic acid, and ketone bodies) [9,77] . It has been reported that
CAFs could support the metastatic behavior of ovarian cancer, causing poor prognosis, through releasing
the chemokine CXCL14 that induced an upregulation of the lncRNA LINC00092 in ovarian cancer cells
[78]
where it determined a glycolytic shift . Glycolytic shift has been reported to induce autophagy-dependent
[79]
chemoresistance to cis-platinum therapy in ovarian cancer .
NcRNAs play a role in cancer development, acting as epigenetic modulator of the expression of oncogenes
or tumor suppressor genes [80,81] , and it is conceivable that ncRNAs released in the tumor microenvironment
also contribute to the dysregulation of autophagy in cancer cells.