miR-21 is an oncogenic miRNA that isoverexpressed in breast cancer. miR-21 targets tumour suppressor gene such asTropomysin (TPM1) and phosphatase and tensin homolog (PTEN) by binding to the3’UTR of TPM1, to exhibit the breast cancer progression in MCF-7 cell line.Anoikis cell death thus been inactivated as well. Therefore, theresearchers concluded that SM1 upregulationof miR-21 can promote oncogenic effect (Vimalraj et al., 2013).The highexpression of oncogenic miR-27a in breast cancer cells often enhance the cellsurvival and prevent the process of cell death from taking place by targeting Forkheadbox protein O1 (FOXO1), which promotes apoptosis upon its high expression (Guttilla & White, 2009). Besides, Zinc finger and BTB domaincontaining 10 (ZBTB10), a protein encoded by ZBTB10 gene, SM2 also acts as a direct target ofmiR-27a to promote angiogenesis by regulating the breastcancer stem cell properties (Wang & Luo, 2015).
The oncogenicmiR-155 is usually overexpressed in breast tumour tissues. It allows theviability of cancer cells and decreases chemosensitivity to anticancer drugs whenmiR-155 is upregulated. miR-155 can suppress the cytokine signalling 1 (SOCS1)which acts as an anti-inflammatory cytokine and mediate the activation ofSTAT3. Besides its role in cancer and inflammation, upregulation of miR-155also inhibits apoptosis by targeting caspase-3, an effector caspase for cellexecution (Wang & Luo, 2015).As another example of oncogenicmiRNA, miR-181a was found to inhibit anoikis pathways and increase the survivalrate in breast cancer cell lines as well. The authors of this study predictedthat Bim, an apoptotic protein, will only be inhibited at the translationallevel instead of mRNA transcriptional level as there was no degradation of BimmRNA (M.
A. Taylor et al., 2013).From previous study, downregulationof miR-18a together with overexpression of hypoxia-inducible factor 1? (HIF1A)activity encouraged the metastasis of basal breast cancer type to other organs.Based on this statement, the researchers then inferred SM1 thatmiR-18a plays a role to inhibit the tumour progression and metastasis by limitingactivity of HIF1A and responding to hypoxia (Krutilina et al., 2014).Tumour suppressivemiR-124 was found to be silenced in the tumour tissues including breast cancertissues therefor enhancing the cell reproduction or cell cycle throughactivation of cyclin-dependant kinase 6 (CDK6). Overexpression ofmiR-124 was used to inhibit metastasis in breast cancer cells and act as atreatment of cancer.
SM2 miR-124 reduced activity of some pro-metastasis compounds, such as connectivetissue growth factor (CTGF), ras homolog gene family member G(RhoG), integrin-?1 (ITGB1), and Rhoassociated coiledcoilcontaining protein kinase 1 (ROCK1) directly (Lv et al., 2011).miR-145 isnormally downregulated n breast cancer cells. Tumour suppressive miR-145 directlytargets the insulin receptor substrate-1 (IRS-1) and inhibit celldifferentiation and proliferation. miR-145 downregulated expression of bothestrogen receptor-? (ER-?) and rhotekin protein (RTKN), which induced cancercell death. miR-145 also contribute to prevent epithelial-mesenchymaltransition (EMT) in breast cancer cell line through octamer-bindingtranscription factor 4 (Oct4) blockage (Wang & Luo, 2015).Meanwhile,miR-200b was found to be one of the miRNA that promotes anoikis in MDA-MB-231breast cancer cell line.
Transfection of miR-200b mimics showed a positiveanoikis effect by downregulating Pin1 expression (X. Zhang et al., 2013).
miR-200c is one ofthe tumour suppressor miRNA which normally has low expression level in breastcancer stem cells and mammary gland stem cells. Overexpression of miR-200c caninhibit migration and invasion as well as reverse anoikis resistance. Moesin(MSN) and extracellular matrix protein fibronection 1 (FN1) were directlytargeted by miR-200c in breast cancer cell line which inhibited the migrationof cells. Additionally, neutrophic receptor tyrosine kinase 2 (TrkB) were alsofound to be downregulated by miR-200c to promote anoikis. (Howe et al., 2011).In tumour tissuesof breast cancer, miR-205 has lower expression compared to normal breasttissues. miR-205 is one of the tumour suppressor miRNA that targets Receptortyrosine-protein kinase erbB-3 (ErbB3) and Vascular endothelial growth factor A(VEGFA) which are protein kinase and signal protein for vessel formationrespectively that participate in tumour formation and metastasis.
Both ErbB3and VEGFA were negatively regulated when miR-205 is overexpressed in SM3 MCF-7breast cancer cell line to inhibit further cell proliferation of cancer cellsas well as to induce cell death (Vimalraj et al., 2013). miR-335 acts as atumour suppressor by targeting SRY-related HMG-box 4 (SOX4). This causes lessmigration and invasion of breast cancer cells resulting in overall reducedmetastasis. miR-335 was also found to promote apoptosis by mediating with breastcancer 1 (BRCA1) activators which include ER-?, IGF1 and Sp1, and ID4 repressorat the same time (Wang & Luo, 2015).
miR-223 is known as an tumoursuppressive miRNA. Initially, miR-223 was found to be highly expressed instroma cells but absent in tumour cell line in cultures. The highly-expressedof miR-223 in the tumour cells target for STAT5A, an important protein that promotesmigration of cancer cells, and induce cell death. Those miR-223 transfected tumourcells in controlled medium with STAT5A proteins showed an increase level ofanoikis (Pinatel et al., 2014).miR-186-5p was found to have oncogenicproperties of miRNA in colon cancer cells and tissues.
Higher expression ofmiR-186-5p in colorectal cancer tissues and cell lines promotes cellproliferation and tumour formation upon the alteration in cell cycles. Not onlythat, the tumour inhibitor gene FAM134B was downregulated in colon cells in thepresence of miR-186-5p (Islam et al., 2017).
In gastric cancercells and tissues, expression of miR-93 was significantly high. Thus, the studystated that miR-93 increase cell proliferation, migration and invasion,angiogenesis. The researchers also found that miR-93 targets tissue inhibitorof metalloproteinase 2 (TIMP2). In the study of Guan and partners, they usedsiRNA to knockdown the TIMP2 gene and they identified the oncogenic effect asmiR-93 transfected in gastric cancer cells. Therefore, they concluded thatmiR-93 acts oncogenically and mediates formation of tumours (Guan et al., 2017).
In recent study, miR-17-92 is one ofthe oncogenic miRNA that usually overexpress in many cancer cells thatmediating cell proliferation in pancreatic cancer. miR-17-92 targets theretinoblastoma-like protein 2 (RBL2), one of the tumour suppressive proteinthat associate with transcription factor E2F4 and block the promoter regions ofE2F target genes. Upregulated of miR-17-92 can interrupt the RBL2/E2F4 complexand allow the transcription and proliferation processes (Zhu et al., 2018). Anoikis resistant cells in cancer canbe fatal by leading to the formation of malignant tumour and metastasis. A studyin human esophageal adenocarcinoma (EA) cells revealed miR-26a, a commonlydownregulated miRNA in tumours, to have tumour suppressive characteristic byparticipating in anoikis resistant mechanism and cell cycle regulation bytargeting retinoblastoma 1 (Rb1) proteinSM1 interactswith E2F1, elongation factor to inhibit E2F1 activate the transcription (Y.-F. Zhang et al.
, 2013).In tumourmicroenvironment, miR-26a is usually low-expressed in HCC tissues. Overexpressionof miR-26a can act tumour suppressively to induce apoptosis and activation ofcaspase-3, the effector caspase.
Integrin alpha-5 (ITGA5) is the proteinencoded by ITGA5 gene, inhibits anoikis by promoting tumour invasion, isone of the targets of miR-26a. When miR-26a was upregulated, ITGA5 proteinlevel was decreased, thus increasing the activity of anoikis in HCC cells (Xiang Zhang et al., 2015).
miR-30a was foundto suppress different types of human cancer. A study reported that overexpressionof miR-30a decreases the migration and invasion of hepatocellular carcinoma(HCC) cells. miR-30a targets Beclin1 and Atg5, which subsequently inhibitsautophagy in HCC (Fu et al., 2018). miR-145 is anothertumour suppressor miRNA that prevents the activity of cell proliferation andinvasion when it is overexpressed in oesophageal squamous cell carcinoma(ESCC). Additionally, upregulation of miR-145 also induced anoikis in KYSE-410cell line but no effect in EAC cells. Thus, EAC cells are mostly protected bymiR-145 to resist anoikis but miR-145 still contribute to heal the wounds (Derouet et al., 2014).
Tumour suppressor gene that regulatesmiR-204 in the chromosome was absent in the chromosome of the patient with ovariancancer. Positively regulated miR-204 in cancer cells helps to restoreanoikis sensitivity, thus decrease tumour activity of migration and invasion, thateventually lead to downregulation of brain-derived neurotrophic factor (BDNFSM2 )and prohibition of activating mitochondria-dependent PI3K/AKT signallingpathway. This causes the cancer cells in epithelial ovarian cancer (EOC) toundergo anoikis. In addition, miR-204 was found to decrease resistance towardsanoikis in HO-8910 and SKOV-3 cell by p-AKT signing pathway inactivation (Yan et al., 2015).