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.