miR-21 is an oncogenic miRNA that is
overexpressed in breast cancer. miR-21 targets tumour suppressor gene such as
Tropomysin (TPM1) and phosphatase and tensin homolog (PTEN) by binding to the
3’UTR of TPM1, to exhibit the breast cancer progression in MCF-7 cell line.
Anoikis cell death thus been inactivated as well. Therefore, the
researchers concluded that SM1 upregulation
of miR-21 can promote oncogenic effect (Vimalraj et al., 2013).
expression of oncogenic miR-27a in breast cancer cells often enhance the cell
survival and prevent the process of cell death from taking place by targeting Forkhead
box protein O1 (FOXO1), which promotes apoptosis upon its high expression (Guttilla & White, 2009). Besides, Zinc finger and BTB domain
containing 10 (ZBTB10), a protein encoded by ZBTB10 gene, SM2 also acts as a direct target of
miR-27a to promote angiogenesis by regulating the breast
cancer stem cell properties (Wang & Luo, 2015).
miR-155 is usually overexpressed in breast tumour tissues. It allows the
viability of cancer cells and decreases chemosensitivity to anticancer drugs when
miR-155 is upregulated. miR-155 can suppress the cytokine signalling 1 (SOCS1)
which acts as an anti-inflammatory cytokine and mediate the activation of
STAT3. Besides its role in cancer and inflammation, upregulation of miR-155
also inhibits apoptosis by targeting caspase-3, an effector caspase for cell
execution (Wang & Luo, 2015).
As another example of oncogenic
miRNA, miR-181a was found to inhibit anoikis pathways and increase the survival
rate in breast cancer cell lines as well. The authors of this study predicted
that Bim, an apoptotic protein, will only be inhibited at the translational
level instead of mRNA transcriptional level as there was no degradation of Bim
mRNA (M. A. Taylor et al., 2013).
From previous study, downregulation
of 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 that
miR-18a plays a role to inhibit the tumour progression and metastasis by limiting
activity of HIF1A and responding to hypoxia (Krutilina et al., 2014).
miR-124 was found to be silenced in the tumour tissues including breast cancer
tissues therefor enhancing the cell reproduction or cell cycle through
activation of cyclin-dependant kinase 6 (CDK6). Overexpression of
miR-124 was used to inhibit metastasis in breast cancer cells and act as a
treatment of cancer.SM2
miR-124 reduced activity of some pro-metastasis compounds, such as connective
tissue growth factor (CTGF), ras homolog gene family member G
(RhoG), integrin-?1 (ITGB1), and Rhoassociated coiledcoil
containing protein kinase 1 (ROCK1) directly (Lv et al., 2011).
normally downregulated n breast cancer cells. Tumour suppressive miR-145 directly
targets the insulin receptor substrate-1 (IRS-1) and inhibit cell
differentiation and proliferation. miR-145 downregulated expression of both
estrogen receptor-? (ER-?) and rhotekin protein (RTKN), which induced cancer
cell death. miR-145 also contribute to prevent epithelial-mesenchymal
transition (EMT) in breast cancer cell line through octamer-binding
transcription factor 4 (Oct4) blockage (Wang & Luo, 2015).
miR-200b was found to be one of the miRNA that promotes anoikis in MDA-MB-231
breast cancer cell line. Transfection of miR-200b mimics showed a positive
anoikis effect by downregulating Pin1 expression (X. Zhang et al., 2013).
miR-200c is one of
the tumour suppressor miRNA which normally has low expression level in breast
cancer stem cells and mammary gland stem cells. Overexpression of miR-200c can
inhibit migration and invasion as well as reverse anoikis resistance. Moesin
(MSN) and extracellular matrix protein fibronection 1 (FN1) were directly
targeted by miR-200c in breast cancer cell line which inhibited the migration
of cells. Additionally, neutrophic receptor tyrosine kinase 2 (TrkB) were also
found to be downregulated by miR-200c to promote anoikis. (Howe et al., 2011).
In tumour tissues
of breast cancer, miR-205 has lower expression compared to normal breast
tissues. miR-205 is one of the tumour suppressor miRNA that targets Receptor
tyrosine-protein kinase erbB-3 (ErbB3) and Vascular endothelial growth factor A
(VEGFA) which are protein kinase and signal protein for vessel formation
respectively that participate in tumour formation and metastasis. Both ErbB3
and VEGFA were negatively regulated when miR-205 is overexpressed in SM3 MCF-7
breast cancer cell line to inhibit further cell proliferation of cancer cells
as well as to induce cell death (Vimalraj et al., 2013).
miR-335 acts as a
tumour suppressor by targeting SRY-related HMG-box 4 (SOX4). This causes less
migration and invasion of breast cancer cells resulting in overall reduced
metastasis. miR-335 was also found to promote apoptosis by mediating with breast
cancer 1 (BRCA1) activators which include ER-?, IGF1 and Sp1, and ID4 repressor
at the same time (Wang & Luo, 2015).
miR-223 is known as an tumour
suppressive miRNA. Initially, miR-223 was found to be highly expressed in
stroma cells but absent in tumour cell line in cultures. The highly-expressed
of miR-223 in the tumour cells target for STAT5A, an important protein that promotes
migration of cancer cells, and induce cell death. Those miR-223 transfected tumour
cells in controlled medium with STAT5A proteins showed an increase level of
anoikis (Pinatel et al., 2014).
miR-186-5p was found to have oncogenic
properties of miRNA in colon cancer cells and tissues. Higher expression of
miR-186-5p in colorectal cancer tissues and cell lines promotes cell
proliferation and tumour formation upon the alteration in cell cycles. Not only
that, the tumour inhibitor gene FAM134B was downregulated in colon cells in the
presence of miR-186-5p (Islam et al., 2017).In gastric cancer
cells and tissues, expression of miR-93 was significantly high. Thus, the study
stated that miR-93 increase cell proliferation, migration and invasion,
angiogenesis. The researchers also found that miR-93 targets tissue inhibitor
of metalloproteinase 2 (TIMP2). In the study of Guan and partners, they used
siRNA to knockdown the TIMP2 gene and they identified the oncogenic effect as
miR-93 transfected in gastric cancer cells. Therefore, they concluded that
miR-93 acts oncogenically and mediates formation of tumours (Guan et al., 2017).In recent study, miR-17-92 is one of
the oncogenic miRNA that usually overexpress in many cancer cells that
mediating cell proliferation in pancreatic cancer. miR-17-92 targets the
retinoblastoma-like protein 2 (RBL2), one of the tumour suppressive protein
that associate with transcription factor E2F4 and block the promoter regions of
E2F target genes. Upregulated of miR-17-92 can interrupt the RBL2/E2F4 complex
and allow the transcription and proliferation processes (Zhu et al., 2018).
Anoikis resistant cells in cancer can
be fatal by leading to the formation of malignant tumour and metastasis. A study
in human esophageal adenocarcinoma (EA) cells revealed miR-26a, a commonly
downregulated miRNA in tumours, to have tumour suppressive characteristic by
participating in anoikis resistant mechanism and cell cycle regulation by
targeting retinoblastoma 1 (Rb1) proteinSM1 interacts
with E2F1, elongation factor to inhibit E2F1 activate the transcription (Y.-F. Zhang et al., 2013).
microenvironment, miR-26a is usually low-expressed in HCC tissues. Overexpression
of miR-26a can act tumour suppressively to induce apoptosis and activation of
caspase-3, the effector caspase. Integrin alpha-5 (ITGA5) is the protein
encoded by ITGA5 gene, inhibits anoikis by promoting tumour invasion, is
one of the targets of miR-26a. When miR-26a was upregulated, ITGA5 protein
level was decreased, thus increasing the activity of anoikis in HCC cells (Xiang Zhang et al., 2015).
miR-30a was found
to suppress different types of human cancer. A study reported that overexpression
of miR-30a decreases the migration and invasion of hepatocellular carcinoma
(HCC) cells. miR-30a targets Beclin1 and Atg5, which subsequently inhibits
autophagy in HCC (Fu et al., 2018).
miR-145 is another
tumour suppressor miRNA that prevents the activity of cell proliferation and
invasion when it is overexpressed in oesophageal squamous cell carcinoma
(ESCC). Additionally, upregulation of miR-145 also induced anoikis in KYSE-410
cell line but no effect in EAC cells. Thus, EAC cells are mostly protected by
miR-145 to resist anoikis but miR-145 still contribute to heal the wounds (Derouet et al., 2014).
Tumour suppressor gene that regulates
miR-204 in the chromosome was absent in the chromosome of the patient with ovarian
cancer. Positively regulated miR-204 in cancer cells helps to restore
anoikis sensitivity, thus decrease tumour activity of migration and invasion, that
eventually lead to downregulation of brain-derived neurotrophic factor (BDNFSM2 )
and prohibition of activating mitochondria-dependent PI3K/AKT signalling
pathway. This causes the cancer cells in epithelial ovarian cancer (EOC) to
undergo anoikis. In addition, miR-204 was found to decrease resistance towards
anoikis in HO-8910 and SKOV-3 cell by p-AKT signing pathway inactivation (Yan et al., 2015).