miRNAs are highly conserved, endogenous small non-coding RNAs approximately 22 nt in length that bind 3′-UTR of the target mRNA and regulate post-transcriptional gene expression (44). Therefore, the underlying mechanism of miRNA functioning is translational repression or degradation of the target mRNA. Thus, miRNAs play a crucial role in biological events including cell proliferation, differentiation, metabolism and development, signal transduction, apoptotic cell death, host-virus interaction, tumorigenesis and tumor progression via miRNA-RNA-induced silencing complex (miRNA-RISC) (44). Along with mRNAs, miRNAs interact with other noncoding RNAs such as lncRNAs and circRNAs to trigger their decay and this forms a crosstalk and regulatory networks linking the associated target genes (45). miRNAs also participate in the regulation of autophagy genes at the transcriptional and post-transcriptional level and modulate different stages of autophagy (46). miR-30a is identified as one of the first autophagy-related ncRNAs targeting BECN1 in a way that affects cellular processes in various cancer cells (47). Several studies have indicated that dysregulation of autophagy-related miRNAs may be associated with the tumorigenesis of PC.

Several microRNAs can induce autophagy by targeting anti-autophagic genes which subsequently affect the tumorigenesis of pancreatic cancer. The tumour-suppressor role of miR-506 in PDAC has been suggested in a study that triggered autophagic flux and autophagy-related cell death through targeting the STAT3-BCL2-BECN1 axis (48). miR-506 has been reported to downregulate the expression of STAT3 which ultimately led to inhibition of BCL2 and induction of BECN1. Another microRNA, miR-221, also served as a tumour suppressor in pancreatic cancer as it was significantly downregulated in highly invasive pancreatic cancer cells and involved in autophagy-related regulation in tumour cells of PDAC (49). Another interesting study demonstrated that HDAC6 may serve as a target of miR-221 and miR-221 may induce autophagy by suppressing HDAC6 expression and promoting apoptosis in pancreatic cancer cells (50). Histone deacetylase-6 (HDAC6) participates in the clearance of aggresomes by helping in the retrograde transport of autophagosomes and lysosomes. Cells need both HDAC6 and microtubule cytoskeleton for recruitment of the Atg-group of proteins, damaged aggregates and lysosomes for incorporation into aggresomes and use this transport mechanism to enhance autophagic degradation of aggregated proteins (51). miR-23b can directly target an important component of autophagy, ATG12, and promote autophagy in pancreatic cancer cells (52). Table I shows the list of miRNAs regulating autophagy in pancreatic cancer.

MicroRNA-mediated translational repression of autophagy genes impedes the process of autophagy which can further modulate pancreatic malignancy. miR-29a can act as a potent autophagy inhibitor in pancreatic cancer. miR-29a has been reported to be significantly downregulated in pancreatic cancer cells and it inhibits autophagy when overexpressed (53). Increased accumulation of autophagosomes/autophagolysosomes and autophagy markers LC3B and p62 and decreased autophagosome-lysosome fusion constitutes the manifestation of the blockade of autophagy flux by miR-29a in pancreatic cancer cells. miR-29a acts as a late-stage autophagy inhibitor and restricts autophagosome-lysosome fusion by reducing the expression of autophagy proteins, TFEB and ATG9A, essential for lysosomal function and vesicular trafficking (53). Evidence has shown the prevention of autophagy by miR-137 via targeting the 3′-UTR of ATG5 and negatively regulating ATG5 expression in pancreatic cancer cells (54). miR-7 targets several autophagy-related genes, including LKB1, ULK2, ATG4A and ATG7 and upregulates the LKB1-AMPK-mTOR signaling pathway to reduce the supply of intracellular glucose to glycolysis in pancreatic cancer. Thus, miR-7 can suppress pancreatic cancer progression by inhibiting autophagy steps and vesicle elongation to impair the activity of aerobic glycolysis (55). A tumor-suppressor role of miR-372 has been reported in human pancreatic adenocarcinoma by regulating autophagy, where miR-372 causes the downregulation of ULK1 expression in pancreatic cancer cell lines. Thus, the miR-372/ULK1 axis is involved in pancreatic cancer development by suppressing cancer cell proliferation, migration, invasion and autophagy (56). miR-138-5p can inhibit autophagy and tumour cell growth in pancreatic cancer cells by targeting serum starvation-induced autophagic flux. This particular miRNA directly targets the 3′-untranslated region of autophagy-related gene SIRT1 and suppresses its expression level (57). Another miRNA miR-410-3p targets 3′-UTR sequences of HMGB1, a primary regulator of autophagy that binds to Beclin-1 and modulates Beclin1-PI3KC3 complex formation and is known to be involved in cancer development via interfering with signaling pathways. In the gemcitabine-treated PDAC cells, silencing of miR-410-3p promotes autophagic activation and cell growth and suppresses cell apoptosis. miR-410-3p can also attenuate chemoresistance to gemcitabine by inhibiting HMGB1-induced autophagy in PDAC (58). In addition to these, miR-216a inhibits beclin-1-mediated autophagy in pancreatic cancer and promotes apoptosis of pancreatic cancer cells in response to radiation, thus enhancing the radiosensitivity of pancreatic cancer cells (59). By contrast, miR-29c increases the chemosensitivity of pancreatic cancer cells by inhibiting USP22-mediated autophagy and cell survival by downregulating USP22 (60). There is evidence that upregulated miR-375 suppresses autophagy and promotes apoptosis of acinar cells by negatively regulating ATG7 in pancreatitis (61). However, evidence also suggests downregulation of miR-375 in several types of cancer, including pancreatic cancer, having a role in cancer cell proliferation. Thus, the tumor-suppressive role of miR-375 in pancreatic cancer in the context of autophagy remains to be investigated (62). Similarly, miR-155 affects the PI3K/AKT/mTOR signaling pathway and impairs pancreatic autophagy by targeting Rictor (RPTOR-independent companion of MTOR complex 2) in pancreatitis (63). miR-9 has been reported to be significantly downregulated in PDAC cells and overexpression of miR-9 sensitized PDAC cells to doxorubicin via inhibition of autophagy by directly targeting 3′-UTR of eIF5A2 transcript. eIF5A2 is known to be involved in the proliferation of some cancer cells (64). The microRNA miR-30a directly targets the autophagy genes ATG5 and BECN1 and negatively regulates their expression to suppress autophagy. However, miR-30a expression is suppressed in pancreatic cancer cells by a transcriptional modulator protein YY1 (65,66). Overall, a number of miRNAs function by suppression of autophagy. However, in most of the cases expression of these miRNAs is decreased in pancreatic cancer cells so that they obtain the survival advantage.

lncRNAs are transcripts longer than 200 nucleotides which do not encode proteins. There are over 15,000 lncRNAs present across different species (67). The lncRNA category includes antisense, intronic, intergenic molecules as well as pseudogenes and retrotransposons. Gene regulatory mode of function of lncRNAs is implemented by several mechanisms such as epigenetic modification, aiding the assembly of transcriptional modulators, sponging miRNAs and post-transcriptional modification by interfering RNA-binding proteins to the target genes (68). There are reports that lncRNAs also participate in the regulation of autophagy.

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) functions as a pro-tumorigenic lncRNA that can promote the proliferation and metastasis of pancreatic cancer cells via inducing autophagy. Elevated expression of MALAT1 is associated with poor prognosis of PDAC and modulates several cellular autophagic flux genes including LC3, P62 and LAMP-2. Mechanistically, MALAT1 regulates tumorigenesis through HuR-TIA-1-mediated autophagic activation, both of which are potent regulators of mRNA translation and stability. Silencing of MALAT1 reduces the degradation of LC3 in pancreatic cancer cells and it also limits the formation of autophagosomes in vitro and in vivo. It is found that P62 level increases while LAMP-2 level decreases when MALAT1 is silenced. Therefore, MALAT1 can be said to influence only the degradation of autophagosomes but not the formation of autophagosome or the autophagosome-lysosome fusion (69). Similarly, overexpression of HOTAIR increases the ratio of LC3-II/-I and expression of ATG7 thereby enhancing the formation of autophagosome which further promotes autophagy in pancreatic cancer (70). lncRNAs regulating autophagy in pancreatic cancer are listed in Table II.

lncRNA acts as a sponge for miRNAs and regulates miRNA at the transcriptional level as bioinformatics analysis has identified miRNA recognition elements (MREs) on lncRNA sequences (71). It is demonstrated that PVT1 can act as a ceRNA to sponge miR-20a-5p to upregulate ULK1 at the post-trancriptional level and promote cytoprotective autophagy and cell growth of PDAC cells with increased levels of LC3b-II. Thus, overexpression of oncogenic PVT1 in PDAC is often associated with poor prognosis and provides survival advantage to the chemoresistant pancreatic cancer cells (72). Another oncogenic lncRNA, lincRNA-ROR (linc-ROR) has been identified to be upregulated in pancreatic cancer which acts as a ceRNA by sponging miR-124 and inducing autophagy. Linc-ROR has been reported to be negatively correlated with miR-124 expression in PDAC tissues and miR-124 directly targets PTBP1, a splicing factor that switches the isoform expression of PKM to PKM1 following a higher expression of LC3-II (73). The lncRNA HLA complex P5 (HCP5) can also act as a ceRNA by sponging miR-214-3p to target hepatoma-derived growth factor (HDGF) which leads to the regulation of GEM-resistant pancreatic cancer cell proliferation, invasion, migration, apoptosis, and autophagy. Previous findings showed that the expression of HCP5 is upregulated in pancreatic cancer tissues and negatively modulates miR-214-3p expression. In addition, sh-HCP5 induces Beclin1, LC3-I/-II and a decreased p62 expression whereas the opposite occurred in the case of miR-214-3p inhibitor (74). Similarly, overexpression of HOTAIR increased the ratio of LC3-II/-I and the expression of ATG7, thereby enhancing the formation of autophagosome which further promotes autophagy in pancreatic cancer (70).

The lncRNAs are also involved in the crosstalk between autophagy and apoptosis in pancreatic cancer. For example, long intergenic non-protein coding RNA 1207 (LINC01207) has been reported to be involved in autophagy and apoptosis via the LINC01207/miR-143-5p/AGR2 axis in pancreatic cancer cells (75). Previous findings have shown upregulated expression of LINC01207 and AGR2, while miR-143-5p was downregulated. AGR2 acts as a target gene of miR-143-5p and binding of LINC01207 to miR-143-5p upregulates AGR2 expression. Elevated AGR2 expression also inhibits apoptosis in pancreatic cells by increasing the Bcl-2 expression. Thus, results of that study suggest that silencing of LINC01207 can promote autophagy and apoptosis by sponging miR-143-5p through an increase in LC3-II and Beclin-1 protein expression while reducing the p62, AGR2 and ratio of Bcl-2/Bax expression in pancreatic cancer (75). The aforementioned findings clearly show the importance of lncRNAs in modulating autophagy in pancreatic cancer.

Circular RNAs are an important member of the noncoding RNA family. Circular RNAs (circRNAs) are a group of abundant, conservative and highly stable novel type of endogenous non-coding RNAs that are produced by back-splicing event and form a three-dimensional covalently closed loop structure by linking 3′- and 5′-ends (76). circRNAs can be divided into three types such as exonic circRNAs, intronic circRNAs and exon-intronic circRNAs (77). Previous findings suggest that circRNAs have many biological functions including miRNA sponges, protein sponges, enhancer of protein function, protein scaffolding, protein recruiter and template for translation, and can regulate several biological processes related to tumour development, proliferation, apoptosis, and invasion often through competitive binding (78,79). Recent findings suggest potential ceRNA networks of circRNA and miRNA are involved in the autophagy of PDAC which has been predicted using bioinformatics analysis (80). High expression level of exosomal circ-PED8A was reported to be associated with poor survival rate, lymphatic invasion and TNM stage in pancreatic ductal adenocarcinoma (81). circ-PDE8A inhibits autophagy by acting as a ceRNA for miR-338 to promote invasive metastasis through the MACC/MET/ERK or AKT pathways in PDAC. circ-PDE8A also induces the invasive growth of PDAC cells by upregulating MET and sponging miR-338 to regulate MACC1 (77,81). MACC1 has been shown to induce autophagy via the AMPK-ULK1 signaling pathway (82). Similarly, hsa_circ_103076 and hsa_circ_100435 were upregulated and associated with miR-15a in PC. miR-15a can inhibit pancreatic cancer cell proliferation and also induces autophagy by directly targeting Rictor, a component of mTORC2 (83). Therefore, hsa_circ_103076 and hsa_circ_100435 can induce autophagy via functioning as miR-15a sponge (84). It has also been found that hsa_circ_101717 and hsa_circ_10408 are upregulated in pancreatic cancer tissues and both of them can exert a tumour suppression function by sponging miR-506 which triggers autophagy-related cell death via the STAT3-BCL2-BECN1 axis in PDAC (48). ciRS-7 has been reported to be one of the few oncogenic circular RNAs which can inhibit tumour suppressor miR-7 (85). ciRS-7 has been found to be upregulated in PDAC. In addition, ciRS-7 could inhibit miR-7 activity which affects the proliferation and invasion of PDAC. As mentioned earlier miR-7 can also suppress pancreatic cancer progression via inhibiting the LKB1-AMPK-mTOR autophagy axis. We can assume ciRS-7 may be partly associated in the regulation of autophagy via miR-7 in PDAC (86) (Table II). The field of circular RNA is rapidly developing and the roles of circular RNAs in the regulation of cancer are currently under investigation. Thus, the correlation between circRNAs and their sponge effect on autophagy-related miRNAs can provide new insight into the treatment and prognosis of pancreatic cancer. The regulation of autophagy in pancreatic cancer by ncRNAs is shown in Fig. 3.

Several miRNAs have the ability to modulate autophagy-related proteins and thus regulate different stages of autophagy in cancer. Some miRNAs which participate in autophagy regulation are known to act as marker for tumor diagnosis (77). Several studies have demonstrated that miRNA can regulate radiosensitivity in cancer cells by modulating autophagy. For example, miR-214 increases radiosensitivity by inhibiting ATG12-mediated autophagy (87), while miR-183-5p enhances radio-resistance by targeting ATG5 in colorectal cancer (88). ATG5 is also known to be targeted by miR-137 to inhibit autophagy and chemo-sensitize PC cells to doxorubicin (Dox) (54). BECN1-mediated autophagy inhibition by miR-216a has been reported to increase the radiosensitivity of pancreatic cancer cells, where radiation therapy is a significant approach for patients with unresectable malignancy (59). It has been demonstrated that the miR-9/eIF5A2 axis regulates autophagy in PDAC to increase the anti-cancer effect of doxorubicin in tumor cells (89). Furthermore, miR-29a can function as a novel therapeutic agent as it sensitizes chemo-resistant cancer cells to gemcitabine and decreases the invasive potential of pancreatic cancer cells (53), while miR-410-3p can attenuate chemoresistance to gemcitabine by inhibiting HMGB1-induced autophagy in PDAC (58).

Several lncRNAs are also known to influence radiosensitivity in cancer cells. lncRNA HOTAIR was found to be highly expressed in pancreatic tumour tissues after radiotherapy and knockdown of HOTAIR can increase radiosensitivity of pancreatic cancer cells by regulating autophagy (70). Blockade of autophagy in pancreatic cancer cells can sensitize it to gemcitabine and reduce the activity of pancreatic cancer stem cells (90). lncRNA SNHG14 can enhance gemcitabine resistance in PC by inhibiting cell apoptosis via the SNHG14/miR-101/autophagy axis. SNHG14 has been reported to sponge miR-101 where SNHG14 is upregulated while miR-101 was downregulated in the PDAC tissues. Overexpression of SNHG14 can increase autophagy-related proteins RAB5A and ATG4D, thus enhancing PDAC cell progression (91). Understanding of these interactions between noncoding RNAs and autophagy genes in cancer cells may be helpful to design a potential therapeutic approach for pancreatic cancer patients. There is, however, no reported study on the specific aspects of circular RNAs and their therapeutic implications involving autophagy pathways in pancreatic cancer; mainly due to the fact that not much work has been performed using such pathways.

Additionally, neoadjuvant-based systemic chemotherapy has also been an important mode of treatment for solid tumours and also for pancreatic cancer, promoting patient survival (92,93). Evidence in breast cancer and osteosarcoma shows that neoadjuvants suppress autophagy and increase drug sensitivity of the malignant cells. Consequently, well-known autophagy inhibitory drugs are being used as neoadjuvants to increase the cytotoxic effect of anti-cancer drugs or radiotherapy (94,95). We have seen thus far that noncoding RNAs emerged as key regulators of autophagy and it is imperative that there be cross-talk between neo-adjuvant chemotherapy, ncRNAs and autophagy in cancer (96–98). However, to the best of our knowledge, there has not been a single report for similar interaction studies in pancreatic cancer. Therefore, the field holds true promise to have these interactions explored in order to have meaningful explanation of prognosis and treatment of pancreatic cancer. There could be two possibilities: i) noncoding RNAs can be a predictive biomarker of neoadjuvant therapy response. For example, lncRNAs, microRNAs or circRNAs that promote autophagy can be a marker for resistance to neoadjuvant therapy or ii) noncoding RNAs that are known as important regulators of autophagy could serve as novel therapeutic targets for systematic treatment with neoadjuvant therapy molecules.