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ANXA2
Annexins are multifunctional proteins having ability to bind phospholipids in the presence of calcium
ions. It plays important role in cytoskeleton dynamics, signal transduction, and membrane trafficking.
Due to these associated phenomenon annexins are involved in the pathophysiological condition of various
diseases including cancer [115] . Annexin 2 has annexin core structure (highly conserved), N terminal domain
(highly variable), calcium-dependent lipid binding region, RNA-binding helices, F-actin binding site and
[116]
C terminal . Phosphorylation of annexin 2 protein is essential for its multi-functions. In response to cell
transformation, Src kinase phosphorylates annexin 2 (45 phosphorylation sites are known) mainly at the
N terminal domain or the central domain [116] . Phosphorylation of Tyr23 residue in annexin 2 proteins has
[117]
been associated with tumor cell adhesion, angiogenesis, invasion, motility, progression, and proliferation .
Annexin 2, Tyr23 phosphorylation mediated STAT3 phosphorylation is known to involve in glucocorticoid
resistance in cancer cells [118] . Annexin 2 induce coilin disruption/chromosome instability mediated cellular
chemo-resistance in cancer cells [119] . ANXA2 and tenascin-C protein interaction mediated activation of
PI3K/Akt/NF-κB signaling pathway is involved in drug resistance in prostate cancer [119] . Moreover, annexin
2 is also known to involve in radiotherapy and immunotherapy in different cancer cells.

Potassium calcium-activated channel subfamily N member 3
A potassium channel, potassium calcium-activated channel subfamily N member 3 (KCNN3) belongs to
2+
a trivial Ca -activated potassium channel family. KCNN3 have been reported for its role in solid tumor
progression [120] . KCNN3 regulates cell membrane potential in melanoma and breast cancer cells [120] . Cell
migration and invasiveness also partially regulated by P2X purinoceptor 7 and KCNN3. Transient receptor
potential channel 1 and calcium release-activated calcium channel protein 1 with KCNN3 regulates
store-operated calcium entry (SOCE)-dependent cell migration [121] . Upregulation of KCNN3 is positively
associated with bortezomib-resistant myeloma cells which induce drug resistance [120] .

Migration and invasion enhancer 1
Migration and invasion enhancer 1 (MIEN1) gene also known as C35, is a novel gene situated subsequent
to the cluster of differentiation 340 (CD340) in the 17q12 amplicon of the humanoid chromosome [122] . The
gene has unusual potential to increase tumor cell migration and invasion. MIEN1 expresses differentially in
normal cells and cancer cells [123] . Regulation of MIEN1 by miRNAs may permit better targeting strategies
to overcome the respective ailment. The hsa-miR-940 (miR-940) has been reported for their high expression
levels in commemorated normal cells compared to tumor cells [123] . A study reported that hsa-miR-940
directly targets MIEN1 RNA and alters its downstream effectors in prostate cancer [123] . Inactivation of
MIEN1 by miR-940 inhibits cell migration and invasion, diminished cell anchorage-independent growth
aptitude and initiates overexpression of E-cadherin molecule which overcomes mesenchymal-to-epithelial
transition (MET) process [123] . Another study reported that MIEN1, potassium calcium-activated channel
subfamily N member 3 (KCNN3), and drug resistance in ovarian cancer are significantly associated
with each other [120] . MIEN1 and DNp73 interaction induces chemo-resistance in ovarian cancer [124] .
High levels of MIEN1 significantly promotes phosphorylation of tyrosine 23 (Y23) residue on annexin
A2 (ANXA2) which facilitates the interaction with cellular actin filaments and regulates cell trickling/
cytoskeletal rearrangement through actin transformation [119] . Earlier, it has been reported that ANXA2
expression correlates with poor prognosis and a higher number of chemotherapy cycles which stimulate
chemoresistance [125] . Hypoxia and chemokines facilitate the transformation of human neural stem cells to
[126]
glioma stem cells in presence of MIEN1 . FAK activating protein MIEN1 phosphorylates FAK at Y925
and induced phosphorylation of ERK1/2, Akt and NF-κB [127] [Figure 3]. Previously it has been shown that
FAK phosphorylation promotes overall survival of ovarian cancer patients [128] . MET process also promotes
FAK phosphorylation and enhances taxane resistance in ovarian cancer [128] . High-mobility group box 2
(HMGB2) binding protein interacts with MIEN1 and enhances cancer progression and proliferation [129] .
Silencing of HMGB2, an interacting partner MIEN1 sensitizes head and neck squamous cell carcinoma