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Vidoni et al. J Cancer Metastasis Treat 2021;7:4 I http://dx.doi.org/10.20517/2394-4722.2020.95 Page 15 of 20

of invasive breast cancer [151] . A set of miRNAs modulating autophagy at different steps has been shown the
potential as biomarker and therapeutic target in gastrointestinal cancers [152] . Similarly, the expression of
the autophagy-related lncRNAs LUCAT1, AC099850.3, ZFPM2-AS1, and AC009005.1 has been proposed
as a signature for the prognosis of hepatocellular carcinoma [153] . Additionally, the lncRNAs HULC (which
triggers autophagy in hepatocellular carcinoma) and AC023115.3 (that inhibits autophagy in glioblastoma)
have been proposed as potential biomarkers and therapeutic targets in the respective cancers [154,155] .
Also, circ-ncRNAs might have diagnostic, prognostic, and therapeutic potential, though at present their
mechanism of action is still obscure [156,157] .

However, the data do not consistently prove the net function of the given ncRNAs in promoting or
inhibiting autophagy and cancer, indicating that its action is tumor-context dependent. For instance,
hyper-expression of MEG3 associated with cisplatin chemoresistance in advanced breast cancer and
correlated with poor prognosis [158] . Yet, this same lncRNA acted as a tumor suppressor in ovarian cancer by
upregulating ATG3 and so inducing autophagy [129] .

Taken together, these data point to the need of a thorough assessment of the genetic and epigenetic
signature of the cancer for designing a personalized therapy in the treatment of malignancies affecting
women.

In conclusion, research on the potential exploitation of ncRNAs as therapeutic targets is still at an
embryonal stage, essentially because of the complexity of the network of signaling in which they operate
that makes difficult to define clearly their tumor promoting or tumor suppressive role. When referring
to the impact of ncRNAs on autophagy regulation for therapeutic purposes, another layer of complexity
is given by the double and opposite role of autophagy in cancer development, which again outlines the
importance of the genetic and epigenetic background of the cell as well as of the signals provided by tumor
microenvironment.

Thus, more studies are needed to dissect how the complex network of ncRNAs impacts on the autophagy
process to identify the relevant ncRNA (and the signaling pathway) that could be used as diagnostic/
prognostic biomarker or as therapeutic target. In this regard, it is worth noting that a variety of natural
products (including resveratrol, curcumin, genistein, and epigallocatechin-3-gallate) have been shown
to affect the expression of autophagy genes through the modulation of ncRNAs, and some of these
compounds are under clinical trial evaluation as adjuvant therapeutics in a variety of cancers (reviewed
in [150,159] ).

DECLARATIONS
Acknowledgements
AF is recipient of a post-doctoral fellowship “Paolina Troiano” (id. 24094) granted by Associazione Italiana
per la Ricerca sul Cancro (AIRC, Milan, Italy). LV and ES are PhD students recipient of a fellowship granted
by the Italian Ministry of Education, University and Research (MIUR, Rome, Italy) with the contribution
of Associazione per la Ricerca Medica Ippocrate-Rhazi (ARM-IR, Novara, Italy). CV was supported with a
post-doctoral fellowship from Università degli Studi del Piemonte Orientale “Amedeo Avogadro” (id. 1412)
granted by Fondazione Cassa di Risparmio di Torino (CRT, Torino, Italy). AS was supported with a short-
term fellowship granted by Consorzio InterUniversitario per le Biotecnologie CIB (Trieste, Italy).

Authors’ contributions
Made the literature search and drafted the manuscript: Vidoni C, Vallino L, Ferraresi A, Secomandi E
Made the literature search and prepared the Tables: Salwa A, Chinthakindi M, Galetto A
Contributed to drawing the figures: Vidoni C, Vallino L
Revised and finalized the manuscript: Dhanasekaran DN, Isidoro C