Molecular determinants of response to 5-fluorouracil-based chemotherapy in colorectal cancer: The undisputable role of micro-ribonucleic acids

Table 1 Summary of studies evaluating the association of different micro-ribonucleic acids with 5-fluorouracil sensitivity or resistance in colorectal cancer

Ref.	miRNA	CRC source	miRNA target	miRNA effect on 5-FU treatment	miRNA-related pathways (KEGG Identifier)[89]	Other findings
Zhang et al[82]	miR-24	HCT116, RKO, SW480, and SW48 cell lines	Downregulation of RNA binding protein DND1 expression	Overexpression enhanced the chemosensitivity of SW48 cell lines	Fatty acid biosynthesis (00061). Proteoglycans in cancer (05205). Cell cycle (04110). Glycosaminoglycan biosynthesis-keratan sulfate (00533). Pancreatic cancer (05212)	miR-24 acted as a tumor suppressor
Zhang et al[83]	miR-361	HCT116 and HT29	Forkhead box M1 (FOXM1)	Overexpression increased chemosensitivity via modulation of FOXM1-ABCC5/10	Adherens junction (04520). Proteoglycans in cancer (05205). Protein processing in the endoplasmic reticulum (04141). miRNAs in cancer (05206). ECM-receptor interaction (04512)	ATP binding cassette subfamily C members 5 and 10 (ABCC5/10) were the downstream effectors of miR-361
Xu et al[84]	miR-375-3p	Tissue and cells	YAP1 and SP1	Overexpression enhanced the chemosensitivity	Hippo signaling pathway (04390). Lysine degradation (00310). Protein processing in the endoplasmic reticulum (04141). Proteoglycans in cancer (05205). Viral carcinogenesis (05203)	Low miR-375 expression was strongly correlated with poor overall survival in CRC patients
Lv et al[85]	miR-133b	Tissue and cells	H3K79me2	Overexpression enhanced the chemosensitivity and reduced CRC stemness	Sulfur relay system (04122). ECM-receptor interaction (04512)	miR-133b overexpression suppressed DOT1L-mediated H3K79me2 modification of stem cell genes
Zhao et al[41]	miR-552	5-FU-resistant tissues and cells	SMAD2 cascade	Overexpression decreased chemoresistance and miR-552 inhibition led to increased chemoresistance	Fatty acid degradation (00071). Fatty acid metabolism (01212). Fatty acid elongation (00062). Biosynthesis of unsaturated fatty acids (01040). TGF-beta signaling pathway (04350)	Expression of miR-552 downregulated in 5-FU-resistant tissues and cells that were regulated by dMMR
Liu et al[88]	miR-543	HCT8/FU	Phosphatase and tensin homolog/ PI3K/ protein kinase B (PTEN/PI3K/AKT)	Downregulation enhanced chemosensitivity	TGF-beta signaling pathway (04350). Signaling pathways regulating pluripotency of stem cells (04550). FoxO signaling pathway (04068). Transcriptional misregulation in cancer (05202). Hippo signaling pathway (04390)	miR-543 enhanced chemoresistance by downregulating expression of PTEN, which negatively regulated AKT activation
Zhao et al[89]	miR-1260b	HCT116	Cell death 4 was a direct target of miR-1260b inhibitor	Inhibition of miR-1260b enhanced chemosensitivity	Wnt signaling pathway (04310). Hippo signaling pathway (04390). Central carbon metabolism in cancer (05230). Adherens junction (04520).Lysine degradation (00310)	miR-1260b inhibitor reduced proliferation and increased apoptosis while downregulating cell death 4, phosphorylated-Akt, and phosphorylated-extracellular-signal-regulated kinase (p-ERK) expression
Guo et al[90]	miR-191	Beta-elemene on colorectal carcinoma HCT116 and HT29	Expression of kinases, including Wnt3a and β-catenin	Downregulation of miR-191 improved chemoresistance	Colorectal cancer (05210). Lysine degradation (00310). Steroid biosynthesis (00100). Hippo signaling pathway (04390). Transcriptional misregulation in cancer (05202)	Beta-elemene downregulated miR-191 and thereby inhibited the Wnt/β-catenin pathway
Cao et al[31]	miR-761	HT29	FOXM1	Overexpression increased chemosensitivity	Glycosphingolipid biosynthesis. Lacto and neolacto series (00601). Mucin Type O-Glycan biosynthesis (00512). Biosynthesis of unsaturated fatty acids (01040)	MiR-761 expression negatively associated with FOXM1 expression and elevated FOXM1 expression suppressed cell proliferation, colony formation and invasion
Kong et al[91]	miR-195	5-FU-resistant HCT116 and SW480	PI3K/AKT and NF-κB pathways	Overexpression enhanced chemosensitivity	Viral carcinogenesis (05203). Hippo signaling pathway (04390). Proteoglycans in cancer (05205). Adherens junction (04520). Pathways in cancer (05200). Fatty acid degradation (00071)	Schizandrin A (SchA) sensitized 5-FU-resistant cells by upregulating miR-195, which inhibited PI3K/AKT and NF-κB pathways
Que et al[92]	miR-874-3p	Tissue and cells	Transcriptional co-activators YAP and TAZ of the Hippo signaling pathway	Overexpression enhanced chemosensitivity		miR-874-3p indirectly inactivated TEAD transcription
Liu et al[79]	miR-135b and miR-182	5-FU resistant Cell lines	ST6GALNAC2 via PI3K/AKT pathway	Overexpression of these two miRNAs increased drug resistance	miR-135b: Hippo signaling pathway (04390). Thyroid hormone signaling pathway (04919). Steroid hormone biosynthesis (00140). Signaling pathways regulating pluripotency of stem cells (04550) cGMP-PKG signaling pathway (04022) miR-182. Fatty acid biosynthesis (00061). Viral carcinogenesis (05203). Adherens junction (04520). Cell cycle (04110). Pancreatic cancer (05212)	miR-135b and miR-182 overexpression were seen in 5-FU resistance cell lines
Zhao et al[32]	miR-15b-5p	Tissue and cells	NF-κB pathway and XIAP	Overexpression decreased chemoresistance	Fatty acid biosynthesis (00061). Fatty acid metabolism (01212). Viral carcinogenesis (05203). Hippo signaling pathway (04390). Adherens junction (04520)	miR-15b mediated apoptosis regulation by negative regulation of NF-κB1 and kinase complexes IKK-α and also targeting anti-apoptosis protein XIAP
Ye et al[40]	miR-1290	Tissue and cells	hMSH2	Inhibition decreased chemoresistance	Proteoglycans in cancer (05205). Fatty acid degradation (00071). ErbB signaling pathway (04012). Signaling pathways regulating pluripotency of stem cells (04550). Estrogen signaling pathway (04915)	miR-1290 was positively correlated with dMMR status and predicted poor prognosis in stage II and III colon cancer patients who received 5-FU
Ren et al[34]	miR-196b-5p	Tissue and cells	SOCS1 and SOCS3 of STAT3 signaling pathway	Downregulation increased chemosensitivity and ectopic expression yielded the opposite effect	Adherens junction (04520). TGF-beta signaling pathway (04350). Proteoglycans in cancer (05205). Hippo signaling pathway (04390). Glycosaminoglycan biosynthesis. Keratan sulfate (00533)	Silencing miR-196b-5p suppressed spheroids formation ability and expression of stem cell factors and enhanced the apoptosis induced by 5-FU. Overexpression of this microRNA correlated with poor survival
Xu et al[60]	miR-330	Tissues and cell	TYMS	Ectopic expression decreased cell proliferation and enhanced chemosensitivity	Adherens junction (hsa04520). ECM-receptor interaction (04512). Thyroid hormone signaling pathway (04919). Proteoglycans in cancer (05205). Hippo signaling pathway (04390)	miR-330 affected thymidylate synthase (TYMS) in the cell apoptosis pathway
Yu et al[34]	miR-125b	Tissues and cell	CXCL12/CXCR4 and Wnt/β-catenin signaling	Expression interfered with chemoresistance	Fatty acid biosynthesis (00061). Fatty acid metabolism (01212). Hippo signaling pathway (04390). Other types of O-glycan biosynthesis (00514). Lysine degradation (00310)	Overexpression of miR-125b triggered epidermal mesenchymal transition and invasion
Jiang et al[93]	miR-577	5-FU resistant SW480 cells	Heat shock protein 27 (HSP27)	Ectopic expression enhanced chemosensitivity	Lysine degradation (00310). Mucin Type O-Glycan biosynthesis (00512). Viral carcinogenesis (05203). p53 signaling pathway (04115). Colorectal cancer (05210)	Restoration of miR-577 suppressed proliferation and induced a G0/G1 cell cycle arrest
Fu et al[94]	miR-20b	5-FU-sensitive (HCT116) and -resistant (HCT116-R)	ADAM9/EGFR	Expression reduced chemoresistance and induced apoptosis	Prolactin signaling pathway (04917). TGF-beta signaling pathway (04350). FoxO signaling pathway (04068). Pancreatic cancer (05212). Bladder cancer (05219)	miR-20b expressed at lower levels in the 5-FU resistant tissues
Liu et al[95]	miR302a	HCT116 and HT29	Insulin-like growth factor1 receptor (IGF1R)	Expression induced chemosensitivity	Lysine degradation (00310). Wnt signaling pathway (04310). Proteoglycans in cancer (05205). Signaling pathways regulating pluripotency of stem cells (04550). Transcriptional misregulation in cancer (05202)	miR302a enhanced 5FUinduced cell death
Dong et al[96]	miR-429	Tissues and cells	-	Decreased expression correlated with better response	Fatty acid elongation (00062). Fatty acid degradation (00071). Adherens junction (04520). Fatty acid metabolism (01212). Ras signaling pathway (04014)	An increase in miR-429 level was associated with tumor size, metastasis, lymph node invasion and TNM stage
Liu et al[35]	miR-149	5-FU-resistant CRC cells (HCT-8/5-FU and LoVo/5-FU)	FOXM1	Re-expression enhanced chemosensitivity	RNA transport (03013). Spliceosome (03040). Gap junction (04540). Sulfur relay system (04122). Thyroid hormone synthesis (04918)	miR-149 enhanced 5-FU sensitivity by increasing apoptosis
Han et al[97]	miR-874	Tissues and cell line	XIAP	Re-expression enhanced chemosensitivity, inhibited proliferation and enhanced apoptosis	Tyrosine metabolism (00350). Thyroid hormone signaling pathway (04919). Glycosphingolipid biosynthesis. Globo series (00603). Thyroid cancer (05216). Glycosphingolipid biosynthesis. ganglio series (00604)	miR-874 expression negatively correlated with TNM stage and lymph node metastasis
Liu et al[98]	miR-139-5p	HCT-8/5-FU and HCT-116/5-FU	NOTCH-1 and MDR-associated genes	Ectopic expression enhanced chemosensitivity and induced apoptosis	Hippo signaling pathway (04390). Neurotrophin signaling pathway (04722). Glioma (05214). Prostate cancer (05215). Estrogen signaling pathway (04915)	Upregulation of NOTCH-1 repealed miR-139-5p-mediated sensitization to 5-FU
Wu et al[99]	miR-204	HCT116 and SW480	High mobility group protein A2	Overexpression decreased chemoresistance	Steroid biosynthesis (00100). Estrogen signaling pathway (04915). ECM-receptor interaction (04512). Metabolism of xenobiotics by cytochrome P450 (00980). Apoptosis (04210)	miR-204 took action by activation of high mobility group protein A2 and the PI3K/AKT pathway
Li et al[61]	miR-218	HCT116 and HT29 cells	Thymidylate synthase (TS)	Overexpression increased chemosensitivity	Fatty acid biosynthesis (00061). Proteoglycans in cancer (05205). Viral carcinogenesis (05203). Pathways in cancer (05200). p53 signaling pathway (04115)	miR-218 suppressed BIRC5 and TS and promoted apoptosis
Zhang et al[81]	miR-587	Tissues and cell	PPP2R1B	Inhibition decreased chemoresistance	GABAergic synapse (04727). Valine, leucine and isoleucine degradation (00280). TGF-beta signaling pathway (04350). Lysine degradation (00310). Signaling pathways regulating pluripotency of stem cells (04550)	miR-587 inhibited AKT activation
Amankwatia et al[80]	miR-224	isogenic KRAS WT and mutant HCT116 cells	ERK and AKT	Decreased expression increased chemosensitivity	Lysine degradation (hsa00310). Fatty acid metabolism (01212). Glioma (05214). Biosynthesis of unsaturated fatty acids (01040). Fatty acid elongation (00062)	miR-224 target genes altered cell proliferation and invasion as well as epithelial-mesenchymal transition
Zhang et al[75]	miR-520g-3p	Tissues and cell	p21	Inhibition of miR-520g in p53 negative cells increased chemosensitivity.	TGF-beta signaling pathway (04350). Folate biosynthesis (00790). Transcriptional misregulation in cancer (05202). Signaling pathways regulating pluripotency of stem cells (04550)	p53 suppressed the miR-520g expression
Kim et al[74]	miR-96	Tissues and cell	XIAP and UBE2N	Expression modulated chemosensitivity and promoted apoptosis	Adherens junction (04520). ECM-receptor interaction (04512). Prostate cancer (05215). Viral carcinogenesis (05203). Protein processing in the endoplasmic reticulum (04141)	Following 5-FU exposure, the expression of the antiapoptotic regulator (XIAP) and p53 stability regulator (UBE2N) decreased
Li et al[59]	miR-203	5-FU-resistant cell line LoVo/5-Fu	Thymidylate synthase (TYMS)	Inhibition of expression increased chemoresistance and the overexpression increased chemosensitivity	Sulfur metabolism (00920). MAPK signaling pathway (04010). Thyroid hormone signaling pathway (04919)	miR-203 increased the inhibitory effect of 5-FU on tumor growth and suppressed TYMS protein levels
Boni et al[58]	miR-192 and miR-215	Tissue and cells	TYMS	The expression did not affect chemoresistance but overexpression reduced cell proliferation	miR-192: Folate biosynthesis (00790). Wnt signaling pathway (04310). Steroid biosynthesis (00100). Lysine degradation (00310). Signaling pathways regulating pluripotency of stem cells (04550). miR-215: Folate biosynthesis (00790). Estrogen signaling pathway (04915). One carbon pool by folate (00670)	Ectopic expression of these miRNAs was a strong predictor of 5-FU response. The expression did not affect chemoresistance but overexpression reduced cell proliferation

miRNA: Micro-ribonucleic acid; 5-FU: 5-fluorouracil; CRC: Colorectal cancer; TS: Thymidylate synthase; TK: Thymidylate kinase; MMR: Mismatch repair; MDR: Multidrug resistance; DOT1L: Disruptor of telomeric silencing 1-like; ECM: Extracellular matrix; KEGG: Kyoto Encyclopedia of Genes and Genomes; TNM: Tumor, node, metastasis.