Tumor microenvironment-driven microRNA dysregulation: Key interactions in colorectal cancer progression

Table 1 Involved microRNA’s in key alterations of the colorectal cancer microenvironment[14,105,132-149]

miR	Cell type	Conditions	Context (hipoxy/inflammation/acidosis)	Key effect on TME	Ref.
miR-210	Epitelial tumor CRC	Progression tumor and metastasis	Hypoxia-upregulated	Classic “hypoxamiR”: Induced by HIF-1α; promotes adaptation to hypoxia, invasion and resistance	Coronel-Hernández et al[132]
miR-21	Tumor/epithelial cells and exosome-mediated transfer to stromal, endothelial, and immune cells	Primary tumor and progression tumor	Inflammation (IL-6/STAT3) and angiogenesis upregulated	Role as an oncomiR; suppresses PTEN and PDCD4; potentiates IL-6/STAT3 signaling, thereby promoting invasion and metastasis; contributes to the establishment of a pro-angiogenic TME	Lai et al[133]
miR-25-3p	Exosomes released from tumor epithelial cells to target endothelial cells	Progression tumor	Hypoxia/angiogenesis (TME) upregulated	Enhances vascular permeability and angiogenesis through the KLF2/KLF4 axis regulating VEGFR2, ZO-1, occludin, and claudin-5; contributing to the establishment of pre-metastatic niche	Xiong et al[134]
miR-1229	Exosomes released from tumor epithelial cells to target endothelial cells	Progression tumor	Hypoxia/angiogenesis (TME) upregulated	Promotes tube formation by inhibiting HIPK2 and enhancing VEGF	Soheilifar et al[135]
miR-320	Epithelial/estromal (colon) IL-6R/STAT3	Primary tumor and metastasis	Inflammation (CAC) downregulated	Inhibits IL-6R STAT3 signaling and reduces tumorigenesis in colitis-associated CRC	Wu et al[136]; Mjelle et al[137]
miR-590-3p (CAF-exosomal)	CAFs (exosomes) tumoral cells	Progression tumor	Damage response/TME stress upregulated	Confers radioresistance and activates PI3K/AKT; an example of TME remodeling by CAFs	Gou et al[138]
miR-34a	Epithelial cells to tumoral cells	Primary tumor supress metastasis	Hipoxia-inflammation/TME downregulated	p53mt-miR-34a suppresses EMT; IL-6/STAT3 downregulates miR-34a, establishing a pro-inflammatory and pro-EMT feedback loop	Włodarczyk et al[139]; Zhang et al[140]
miR-338-5p	Epithelial	Primary tumor, progression and drug resistance	Hypoxia/inflammation downregulated	Deficiency of miR-338-5p enhances IL-6/STAT3 signaling and confers resistance to oxaliplatin, fostering a pro-inflammatory TME	Valencia-Cervantes and Sierra-Vargas[141]
miR-19a	Epithelial	Progression tumor	Inflammation/survival upregulated (hypoxia conditions)	Suppression of PTEN-PI3K/AKT signaling promotes proliferation and invasion, further sustained by IL-6/STAT3 activation	Rahbar Farzam et al[142]
miR-135b-5p (CAF-exosomal)	CAFs (exosomes) epithelial and endothelial cells	Progression tumor	Hypoxia/inflammation upregulated	Exosomes derived from CAFs upregulate miR-135b-5p, leading to TXNIP suppression and enhanced tumor growth and angiogenesis	Umezu et al[143]; Shao et al[144]
miR-425-5p (exosomal)	Tumor (exosomes) macrophages/T	Progression tumor	Inmunosupression upregulated	Induction of M2-like polarization along with suppression of the pro-inflammatory T-cell response contributes to tumor progression and increased vascular permeability	Feng et al[145]
miR-934 (exosomal)	Tumor (exosomes) macrophages (liver)	Upregulated metastasis	Inflammation/metastasis	Induces M2 polarization and facilitates hepatic metastasis	Zhao et al[105]
miR-128-3p	Tumor (exosomes) epithelial	Primary tumor and progression	Inflammation (STAT3) upregulated	Activation of JAK/STAT3 and TGF-β/SMAD signaling promotes EMT and metastatic progression	Rahbar Farzam et al[142]
miR-9-5p	Epithelial tumoral to SLC9A1/NHE1 (antiport Na+/H+)	Progression tumor and metastasis	Acidosis upregulated	Modulation of NHE1 contributes to extracellular acidification, which in turn facilitates tumor invasion and metastasis	Wang et al[146]
miR-224-5p	Epithelial tumoral (HT29) SLC4A4/NBCe1 (Na+/HCO3-)	Progression	Acidosis upregulated	Repression of HCO3- transport diminishes pH buffering capacity, thereby exacerbating tumor acidosis	Yi and Yu[147]
miR-34a	Epithelial tumoral LDHA (lactate dehydrogenase A)	Primary tumor and progression	Acidosis downregulated	Acidosis suppress p53wt downregulation of miR-34a increases LDHA expression, leading to elevated lactate levels and acidosis; it also promotes EMT and therapy resistance	Li et al[14]; Xiong et al[134]
miR-143	Epithelial tumoral hexokinase 2	Primary tumor overexpresssion metastasis	Acidosis downregulated	Loss of this factor promotes glycolytic flux and lactate accumulation, exacerbating tumor acidosis	Gregersen et al[148]; Guo et al[149]

All the microRNAs have been validated in vitro and in vivo models, as well as in patient samples, except miR-590-3p for those that have only been detected in preclinical models and miR-320 in vivo/patients. miR: MicroRNA; CAF: Cancer-associated fibroblast; CRC: Colorectal cancer; IL: Interleukin; STAT: Signal transducer and activator of transcription; Na⁺: Sodium ion; H⁺: Hydrogen ion; HCO₃^-: Bicarbonate; LDHA: Lactate dehydrogenase A; TME: Tumor microenvironment; CAC: Colitis-associated colorectal cancer; HIF: Hypoxia-inducible factor; VEGFR2: Vascular endothelial growth factor receptor 2; ZO-1: Zonula occludens-1; PI3K: Phosphatidylinositol 3-kinase; AKT: Protein kinase B; JAK: Janus kinase; TGF: Transforming growth factor; pH: Potential of hydrogen.

Table 2 MicroRNA’s associated with colorectal cancer molecular subtype and their clinical relevance[150,151]

CMS class	Molecular features	Frequency (%)	Immune phenotype	Prognosis	miR	Ref.
CMS1: Immune MSI	CIMP (increase); BRAFV600E m; hypermutated; KRASwt; TP53wt	14	Immune activation and infiltration LTC and NK	Intermediate prognosis; good early disease control but poor survival after relapse	miR-625 (increase), miR-31 (increase), miR-155 (increase)	Adam et al[150]
CMS2: Canonical (epithelial differentiation)	CIMP negative; BRAFwt; KRASwt; TP53m	37	WNT and MYC activation. Immune dessert	Best overall	miR-592 (increase), miR-552 (increase)	Adam et al[150]
CMS3: Metabolic	CIMP negative; BRAFwt; KRASm; TP53wt	13	Metabolic deregulation	Poor immunogenicity	miR-625 (increase)	Adam et al[150]
CMS4: Mesenchymal	CIMP negative; BRAFwt; KRASwt	23	Stromal infiltration (macrophages) TGF-β activator-CSC EMT and angiogenesis	Worse and poor survival. Resistant standard treatment	miR-625 (decrease), miR-143 (increase) (CMS4 vs CMS2); miR-200 (decrease), miR-218 (increase)	Adam et al[150]; Gherman et al[151]

CMS: Consensus molecular subtype; CIMP: CpG island methylator phenotype; wt: Wild type; m: Mutation; NK: Natural killer; TGF: Transforming growth factor; CSC: Cancer stem cell; EMT: Epithelial-mesenchymal transition; miR: MicroRNA.

Table 3 MicroRNA’s modulating colorectal cancer survivor and invasive pathways[31,36,37,39,47,53,58-60,63,70-72,76,77,79,82-84,98,124,152-169]

miR	Expression	Study model	Target genes	Modulated pathways	Ref.
miR-145-5p	Downregulated	In vitro	N-RAS and IRS1	Cell proliferation by AKT inactivation	Yin et al[152]
miR-145-5p	Downregulated	In vitro	CDCA3	Cell proliferation, migration, invasion, EMT	Chen et al[84]
miR-145-5p	Downregulated	In vitro	TWIST1	Migration and invasion	Shen et al[153]
miR-145-5p	Downregulated	In vitro	MAPK1	Cell proliferation, migration, and invasion	Yang et al[154]
miR-145-5p	Downregulated	In vitro	SIP1	Cell proliferation, migration, and invasion	Sathyanarayanan et al[155]
miR-145-5p	Downregulated	In vitro	PAK4	Migration and invasion	Sheng et al[59]
miR-145-5p	Downregulated	In vitro and in vivo	p70S6K1	Tumor growth and angiogenesis by HIF-1 and VEGF	Xu et al[156]
miR-145-5p	Downregulated	In vitro and in vivo	LASP1	Invasion and metastasis	Wang et al[58]
miR-145-5p	Downregulated	In vitro	CXCL1 and ITGA2	Cell proliferation and migration	Zhuang et al[60]
miR-16-5p	Downregulated	In vitro and in vivo	PVT1	Cell proliferation, migration, and invasion by VEGFA and p-AKT	Rahmati et al[98]
miR-16-5p	Downregulated	In vitro and in vivo	ITGA2	Apoptosis and tumor growth	Xu et al[36]
miR-16-5p	Downregulated	In vitro	BIRC5	Apoptosis, cell proliferation, and angiogenesis	Aslan et al[47]
miR-16-5p	Downregulated	In vitro	FOXK1	Cell proliferation and angiogenesis by PI3K/AKT/mTOR signaling	Huang et al[37]
miR-16-5p	Downregulated	In vitro and in vivo	HMGA2	Migration, invasion, and EMT by β-catenin pathway	Cai et al[63]
miR-199a-3p	Downregulated	In vitro	PAK4 and BCAR3	Cell proliferation, migration and invasion	Hou et al[70]
miR-199a-3p	Downregulated	In vitro	FN1	EMT by N-cadherin and vimentin	Lin et al[71]
miR-199a-3p	Downregulated	In vitro	NLK	Metastasis	Han et al[72]
miR-199a-3p	Downregulated	In vitro	TGFBR1 and PDGFRB	Cell proliferation by MAPK-signaling	Slattery et al[157]
miR-21-3p	Upregulated	In vitro and in vivo	SMAD7	EMT through the increase of N-cadherin	Jiao et al[39]
miR-21-3p	Upregulated	In vitro	RBPMS	Migration, invasion, and apoptosis by Smad4/ERK signaling	Hou et al[53]
miR-21-5p	Upregulated	In vitro and in vivo	KRIT1	Angiogenesis through β-catenin signaling pathway, VEGFA and CCND1	He et al[31]
miR-21-5p	Upregulated	In vitro and in vivo	PDCD4 and TGFBR2	Stemness promotion by upregulation of β-catenin, c-MYC and cyclin-D1	Yu et al[158]
miR-21-5p	Upregulated	In vitro and in vivo	PTEN	Apoptosis, cell proliferation and invasion	Wu et al[76]; Lin et al[77]
miR-21-5p	Upregulated	In vitro and in vivo	CHL1	Cell proliferation, invasion and tumor growth	Yu et al[79]
miR-21-5p	Downregulated	In vitro	TGFBI	Pyroptosis	Jiang et al[82]
	Downregulated	In vitro	SATB1	Cells sensitive to chemoradiation	Lopes-Ramos et al[83]
miR-4461	Downregulated	In vitro	COPB2	Cell proliferation, migration, and invasion	Chen et al[159]
miR-449a	Downregulated	In vitro	HDAC1, TGFB, SATB2, ADAM10, MYC, and MAPK1	Cell proliferation, invasion and poor survival	Ishikawa et al[160]
miR-519d-3p	Downregulated	In vitro	TROAP	Apoptosis, cell proliferation, migration, and invasion	Ye and Lv[161]
miRNA-31	Upregulated	In vitro	STK40	NF-κB signaling pathway and invasion	Zhu and Xue[162]
miR-200a	Upregulated	In vitro	PTEN	Cell proliferation, migration and invasion	Li et al[163]
miRNA-552	Upregulated	In vitro	PTEN	Poor prognosis	Im et al[164]
miRNA-552	Upregulated	In vitro and in vivo	ADAM28	Cell proliferation, migration and tumor growth	Wang et al[165]
miR-592	Upregulated	In vitro	mTOR and FOXO	Cell proliferation, migration and invasion	Pan et al[166]
miR-708 and miR-31	Upregulated	In vitro	CDKN2B	Cell proliferation, invasion and apoptosis resistance	Lei et al[167]
miR-25	Upregulated	In vitro and in vivo	SIRT6	Metastasis through inhibited LIN28B/NRP1 axis	Wang et al[168]
miR-130b-3p	Upregulated	In vitro and in vivo	CHD9	Cell proliferation and tumor growth	Song et al[169]
miRNA-221	Upregulated	In vitro and in vivo	TP53BP2	Cell proliferation through TP53 inhibition	Ali et al[124]

miR: MicroRNA; mTOR: Mammalian target of rapamycin; AKT: Protein kinase B; EMT: Epithelial-mesenchymal transition; HIF: Hypoxia-inducible factor; VEGF: Vascular endothelial growth factor; p-AKT: Phospho-protein kinase B; PI3K: Phosphatidylinositol 3-kinase; MAPK: Mitogen-activated protein kinase; ERK: Extracellular regulated protein kinases; NF-κB: Nuclear factor kappa-B.

Table 4 MicroRNA’s associated with treatment response and therapeutic outcomes in colorectal cancer[26,86,88,91,93,94,170-186]

miR	Mechanism	Study model	Target	Response therapy	Ref.
miR-153-5p	Overexpression	In vitro	BCL-2	Sensibilize oxaliplatin	He et al[170]
miR-145-5p	Decreased	In vitro	BIRC5, Fli-1	Sensibilize, 5-FU, oxaliplatin	Xie et al[171]
miR-1451	Overexpression	In vitro and in vivo	SNAI1, HDAC4 and ATF4	Sensibilize radiotherapy and 5-FU	Zhao et al[88]; Zhu et al[172]
miR-150-5p	Overexpression	In vitro and in vivo	BIRC5, CASP7, VEGFA	Anti-VEGF	Slattery et al[173]; Chen et al[174]
miR-195-5p	Expression	In vivo	GDPD5	Sensibilize 5-FU	Feng et al[175]
	Overexpression	In vitro	BIRC5, BCL-2, YAP	Sensibilize, doxorrubicin and oxaliplatin	Qu et al[176]; Poel et al[177]
miR20b-5p1	Expression	In vitro and in vivo	CTSS, ADAM9, EGFR, CCND1/CDK4/FOXM1 axis	Sensibilize 5-FU	Fu et al[178]; Yang et al[179]
miR21-3p	Overexpression	In vitro	MDR1 and MRP1	Cisplatin resistance	Dong et al[86]
miR21-5p	Overexpression	In vitro	SATB1, PTEN, MSH2, PDCD4	Chemoresistance (oxaliplatin)	Chen et al[94]
miR497-5p	Overexpression	In vitro and in vivo	KSR1, BCL-2, IGF1-R	Sensibilize 5-FU, oxaliplatin	Poel et al[177]; Wang et al[180]
miR-17-5p	Overexpression	In vitro and in vivo	MFN2, vimentin STAT3, E2F1, HMGA2, SOX4, TWIST1, and EGFR	Resistance oxaliplatin, irinotecan, and fluorouracil	Kim et al[26]; Sun et al[181]
miR-199b-3p; miR-199a-5p	Overexpression	In vitro and in vivo	CRIM1	Resistance cetuximab, sensitive cetuximab	Kim et al[26]; Han et al[93]; Mussnich et al[182]
miR-124	Overexpression	In vitro and in vivo	PRRX1	Sensitive radiotherapy (inhibition PRRX1)	Zhang et al[183]
miR-1226-5p	Overexpression	In vitro	IRF1	Resistance radiotherapy	Choi et al[184]
miR-7-5p	Downregulated	In vitro and in vivo	KLF4	Resistance radiotherapy	Shang et al[185]
miR-16-5p	Downregulated	In vitro	FOXK, PI3K/AKT/mTOR	Resistance radiotherapy	Mousavikia et al[91]
miR-423-5p	Downregulated	In vitro	BCL-2	Resistance radiotherapy	Shang et al[186]

¹Expressed on advanced cancer.

miR: MicroRNA; MDR1: Multidrug resistance-1; MRP1: Multidrug resistance protein 1; PI3K: Phosphatidylinositol 3-kinase; AKT: Protein kinase B; mTOR: Mammalian target of rapamycin; 5-FU: 5-fluorouracil; VEGF: Vascular endothelial growth factor.

Table 5 Mesenchymal stem cell-derived exosome-based strategies for microRNA delivery in colorectal cancer[36,159,187-192]

Exo-miR	Cell delivery	Study model	Mechanism	Ref.
Exo-miR30a; miR222	hCC-MSC	In vitro and in vivo	Growth (increase), migration and metastasis (inhibit MIA3)	Du et al[187]
Exo-miR4461	hBM-MSC	In vitro	The proliferation, migration and invasion by down-regulating COPB2 (decrease)	Chen et al[159]
Exo-miR22-3p	hBM-MSC	In vitro	Proliferation and invasion (RAP2B/PI3K/AKT pathway) (decrease)	Wang and Lin[188]
Exo-miR-16-5p	hBM-MSC	In vitro and in vivo	Proliferation, invasion and migration (downregulating ITGA2) (decrease)	Xu et al[36]
Exo-miR431-5p	hUC-MSC	In vitro and in vivo	Progression (suppress PRDX1) (decrease)	Qu et al[189]
Exo-anti-miR-146b-5p ASO	hUC-MSC	In vitro and in vivo	Proliferation, migration and EMT (inhibition of Smad signaling) (decrease)	Yu et al[190]
Exo-miR-486-5p	hUC-MSC	In vitro	Glycolysis and cell stemness by targeting NEK2 (decrease)	Cui et al[191]
Exo-miR-431-5p	hUC-MSC	In vitro and in vivo	Cell growth and progression by inhibiting PRDX1 (decrease)	Qu et al[189]
1Exo-miR-199a-3p	AMSCs	In vitro and in vivo	Sensitized to chemotherapeutic agents by targeting mTOR pathway	Lou et al[192]

¹Hepatocellular carcinoma.

miR: MicroRNA; ASO: Antisense oligonucleotides; hCC-MSC: Human cancer cells-mesenchymal stem cell; hBM-MSC: Human bone marrow-mesenchymal stem cell; hUC-MSC: Human umbilical cord- mesenchymal stem cell; AMSC: Adipose tissue-derived mesenchymal stem cell; PI3K: Phosphatidylinositol 3-kinase; AKT: Protein kinase B; EMT: Epithelial-mesenchymal transition; mTOR: Mammalian target of rapamycin.