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Eng et al. J Cancer Metastasis Treat 2019;5:69 I http://dx.doi.org/10.20517/2394-4722.2019.021 Page 5 of 13
[25]
to switch from EMT to MET with concurrent inactivation of autophagy in supportive niches . However,
if the new environment is not permissive in situations such as cellular stress or a lack of available growth
factors, the DTCs could exist in a dormant state, possibly by retaining elevated autophagic functions and
delaying MET. Notably, autophagy inhibition in the neoadjuvant setting has also been shown to reduce
[26]
pro-metastasis stromal cells at the premetastatic niche . Future work could be performed to determine
whether inactivation of autophagy is necessary to drive MET of invading tumor cells at distant organs/
tissues, thus providing new impetus for the development of anti-metastasis autophagy inhibitors.

MIRNAS: NONCODING REGULATORS OF AUTOPHAGY AND CANCER METASTASIS
MicroRNAs (miRNAs) are endogenously expressed small non-coding RNAs of 19-25 nucleotides in length,
which negatively regulate gene expression post-transcriptionally. They regulate multiple cellular processes
including proliferation, differentiation and apoptosis. They have been implicated in a growing list of human
[27]
diseases, such as diabetes and cancer .
In the canonical miRNA biogenesis pathway, the primary transcript (pri-miRNA) in the nucleus forms a
characteristic stem loop structure, which is recognized and cleaved by the Drosha/DGCR8 heterodimer
into pre-miRNA. The pre-miRNA hairpin loop is transported into the cytoplasm by Exportin-5, where its
terminal loop is further cleaved by RNA endonuclease III Dicer to generate the mature duplex miRNA.
Either strand can be processed into the final mature single-stranded miRNA, with the strand originating
from the 5’end of the transcript known as 5p, while the strand originating from the 3’end is known as
3p. Association of the mature miRNA duplex with Argonaut proteins (Ago) forms the RNA-induced
silencing complex (RISC), where the guide strand of ~22 nt remains in Ago while the passenger strand gets
degraded [28,29] . Due to the short sequence length of miRNAs, and the fact that their partial complementary
binding to multiple regions of target messenger RNAs (mRNAs) is sufficient to guide the RISC to its target
genes, miRNAs are able to regulate the expression of a myriad of genes that play critical roles in controlling
cellular processes, including autophagy and cancer metastasis.

AUTOPHAGY-REGULATING MIRNAS IN CANCER METASTASIS
Owing to the complexity and dynamic nature of autophagy, past literature that implicated a role of
miRNAs in the regulation of autophagy have been highly discordant even in the same cell type. To
reconcile and put things into perspective, we examined and discuss the opposing roles of miRNA-
regulated autophagy during the invasion phase versus the distant organ/tissue colonization phase of cancer
metastasis.

At the onset of metastasis, cancer cells in the primary tumor first undergo EMT to enable the attached
cancer cells to gain motile traits for invasion of the lymphovascular system. The role of autophagy in cancer
[23]
cell motility and invasion was comprehensively reviewed by Mowers et al. . Suffice to say that many
reports have now demonstrated the elevation in autophagy in cancer cells drives tumor dissemination, and
this may in part be regulated by miRNAs. miRNAs that have been shown to regulate autophagy and cell
migration/invasion in the context of cancer have been summarized in Table 1.

Upregulation in oncogenic miRNAs (oncomiRs) is known to promote tumorigenesis via modulation of
[29]
gene expression of a variety of growth and survival pathways in cancer cells. For instance, elevated levels of
miR-100 and miR-146 are found in cancer cells. Notably, these oncomiRs have been shown to be critical for
the activation of pro-survival autophagy via suppression of the expression of autophagy inhibitory effectors
like the mammalian target of rapamycin (mTOR) and Bcl2, respectively [Figure 1] [30,32,33] . miR-100 and
miR-146 have also been shown to be key EMT effectors that promote metastasis [31,34] , with miR-100
proposed to act through HOXA inhibition , and miR-146 via Notch2 inhibition . Overexpression of
[83]
[84]