*3.3.1 Osteosarcoma*

LncRNA-CASC15 promotes lung metastasis in osteosarcoma by regulating EMT via the Wnt/β-catenin signaling pathway [139] (**Table 3**). MIR205HG also can drive lung metastatic osteosarcoma via regulating the axis of miR-2114-3p/twist family bHLH transcription factor 2 (TWIST2) [140]. miR-485-3p regulated by lncRNA MALAT1 inhibites osteosarcoma glycolysis and lung metastasis by directly suppressing c-MET


*Notes: ESCC: esophageal squamous cell carcinoma; FSCN1: fascin actin-bundling protein 1; VDR: vitamin D receptor; KLF5: Kruppel like factor 5; bHLH transcription factor 2; CDK6: Cyclin Dependent Kinase-6; STAT3: signal transducer and activator of transcription-3; HDAC: histone deacetylase 1; ZEB1: Zinc Finger E-Box Binding Homeobox 1; ROCK1: Rho associated coiled-coil containing protein kinase 1; CRYAB: αB-crystallin; DNMTs: DNA methyltransferase; ERα: estrogen receptor alpha; TET2: ten-eleven translocation 2; IRX1: iroquois homeobox 1; PDK1: phosphoinositide-dependent kinase-1; ST7L: suppression of tumorigenicity 7 like; and BRD4: bromodomain containing 4.*

#### **Table 2.**

*Epigenetic biomarkers in liver and brain metastases of various cancers.*

and AKT3/mTOR signaling, meanwhile, MALAT1 also facilitated lung metastasis of osteosarcomas through miR-202 sponging [141, 142]. Besides, Chen et al. also observed that the LOC100129620/miR-335-3p/CDK6 signaling promoted the lung metastasis of osteosarcoma by mediating the osteosarcoma cells proliferation, macrophage polarization, and angiogenesis [144]. The lncRNA NEAT1/miR-483/STAT3 axis also exerts a crucial role in regulating the lung metastasis process in osteosarcoma, especially in EMT [145]. miR-326 inhibited by SP1/HDAC1 has a great impact on proliferation and metastasis of osteosarcoma through stimulating SMO/Hedgehog pathway [146]. The miR-19a/RhoB/AKT1 network and miR-491/αB-crystallin (CRYAB) axis also may help us to better know the lung metastatic mechanism of osteosarcoma [147, 149]. In Ewing sarcoma, miR-130b directly targets ARHGAP1 to activate a lung metastatic CDC42-PAK1-AP1 positive feedback loop [157].

Additionally, Lillo et al. found estrogen receptor alpha (ERα) was not expressed in osteosarcoma due to promoter DNA methylation. They took Decitabine, a DNA


*Notes: TWIST2: twist family bHLH transcription factor 2; CDK6: Cyclin Dependent Kinase-6; STAT3: signal transducer and activator of transcription-3; HDAC: histone deacetylase 1; ZEB1: Zinc Finger E-Box Binding Homeobox 1; ROCK1: Rho associated coiled-coil containing protein kinase 1; CRYAB: αB-crystallin; DNMTs: DNA methyltransferase; ERα: estrogen receptor alpha; TET2: ten-eleven translocation 2; IRX1: iroquois homeobox 1; PDK1: phosphoinositide-dependent kinase-1; and ST7L: suppression of tumorigenicity 7 like.*

#### **Table 3.**

*Epigenetic biomarkers in lung metastases of various cancers.*

methyltransferase (DNMTs) inhibitor to activate ERα, further inhibiting osteosarcoma growth and lung metastasis [150]. In primary osteosarcoma cells, increased IL-6 expression regulated by DNA demethylation of the promoter of ten-eleven translocation 2 (TET2) promotes lung metastasis in osteosarcoma [152]. Secreted

protein acidic and rich in cysteine (SPARCL1) downregulated by epigenetic promoter DNA methylation in osteosarcoma promotes lung metastasis via canonical WNT/βcatenin signaling activated through stabilization of the WNT–receptor complex [151]. Hypomethylation of iroquois homeobox 1 (IRX1) in osteosarcoma cell lines substantially affected metastatic behavior in vitro, including migration, invasion, and resistance to anoikis and influenced lung metastasis in animal models by upregulating CXCL14/NF-B signaling, according to another study [153].

### *3.3.2 Breast cancer*

In the study by Wang et al. they showed that linc-ZNF469-3 accelerated lung metastasis of triple-negative breast cancer (TNBC) via miR-574-5p-ZEB1, which may be acted as a potential and promising prognostic marker for TNBC patients [154]. MIR31HG, a long noncoding RNA that sponges miRNA-575 to control ST7L expression, suppresses hepatocellular carcinoma proliferation and metastasis [155].
