Table 2.

miRNAs and autophagy in hepatocellular carcinoma cell drug resistance

miRNA	Expression Level in HCC	Effect on autophagy	Involvement in drug resistance	Ref.
miR26a/b	Downregulated in tissues and cell lines (HepG2, Hep3B, MHCC97-H and SMCC-7721), also by chemotherapeutic drugs and autophagy inhibitors	Inhibited autophagy, by targeting the expression of ULK1, the key initiator of autophagy	Sensitized HepG2 cells and tumors to apoptosis induced by DOX through targeting autophagy	[53,54]
miR199a-5p	Downregulated in HepG2 and HuH-7 cells and tissues, also by chemotherapeutic drugs	Inhibited cisplatin-induced autophagy, by interacting with the 3’UTR region of ATG7 transcript (an autophagy related gene)	Protected HepG2 and HuH-7 cells from cisplatin-induced resistance	[56,58]
miR101	Downregulated in cell lines (SMMC-7721, HepG2, Bel-4404, and 97L) and tissues, associated with distant metastasis and related to poor prognosis	Inhibited autophagy, by reducing STMN1, RAB5A, ATG4D and mTOR expression (involved in the phagosome formation)	Sensitized HepG2 cells to apoptosis induced by cisplatin	[61,62]
miR216b	Downregulated in patient plasma and tissues, related to poor prognosis	Inhibited autophagy, by targeting . MALAT1 (an oncogenic long non-coding RNA generally upregulated in HCC that modulates chemosensitivity)	Sensitized BEL-7402/5-FU resistant cells to 5-FU-, DOX- and mitomycin-induced death	[65,66]
miR142-3p	Downregulated in tissues, also by sorafenib treatment	Inhibited sorafenib-induced autophagy by binding to the 3’-UTR of ATG5 and ATG16L1	Sensitized SMCC-7721 and HepG2 cells to sorafenib-induced death	[69,70]
miR21	Overexpressed in patient tissues and in drug-resistant cells	Inhibited autophagy, and downregulated PTEN pathway	miR21-dependent autophagy inhibition contributed to sorafenib resistance in Huh7 and HepG2 cells and HCC tumors developed in mice	[72-74]
miR423-5p	Overexpressed in tissues, also elevated in serum of sorafenib-treated patients, and secreted in high levels from sorafenib-treated cells	Induced autophagy	Proposed as a helpful tool to predict patient response to sorafenib treatment	[77,78]

miRNA: MicroRNA; HCC: Hepatocellular carcinoma; ULK1: Unc-51 like autophagy activating kinase; DOX: Doxorubicin; 3’-UTR: 3’-untranslated region; ATG: autophagy-related protein; STMN1: Stathmin 1; RAB5A: RAS related protein; ATG4D: autophagy-related 4D cysteine peptidase; mTOR: The mammalian target of rapamycin; MALAT1: Metastasis associated lung adenocarcinoma transcript 1; 5-FU: 5-Fluoroacil; PTEN: Phosphatase and tensin homologue.