Biomedicine & Pharmacotherapy 123 (2020) 109725

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Biomedicine & Pharmacotherapy

journal homepage: www.elsevier.com/locate/biopha

SOX2OT, a novel tumor-related long non-coding RNA T

a,b, a,b a a,b a, a,b,
Ying Wang *, Nayiyuan Wu , Xia Luo , Xiaoyun Zhang , Qianjin Liao *, Jing Wang *
a
Department of the Central Laboratory, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha
410013, Hunan, People’s Republic of China
b
Hunan Clinical Research Center in Gynecologic Cancer, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South
University, 283, Tongzipo Road, Changsha 410013, Hunan, People’s Republic of China

A R T I C LE I N FO A B S T R A C T

Keywords: SOX2OT is a long non-coding RNA that is highly expressed in embryonic stem cells. The SOX2OT gene is
Long non-coding RNA comprised of 10 exons and more than two transcription start sites. Dysregulation of SOX2OT is observed in
SOX2OT various tumors, including lung cancer, gastric cancer, esophageal cancer, breast cancer, hepatocellular carci-
Diagnostic biomarker noma, ovarian cancer, pancreatic ductal adenocarcinoma, laryngeal squamous cell carcinoma, cholangiocarci-
Therapeutic target
noma, osteosarcoma, nasopharyngeal carcinoma, and glioblastoma, wherein it typically functions as an onco-
gene and possibly as a tumor suppressor gene. The mechanisms underlying the effects of SOX2OT are complex
and involve multiple factors and signaling pathways. In this review, we describe the current evidence regarding
the role and potential clinical utility of SOX2OT in human cancers.

1. Background tumorigenesis and can function as tumor oncogenes or suppressors

Cancers are a group of malignant diseases that seriously threaten
human health worldwide. The incidence and mortality of cancer are
increasing each year, which is related to population growth and aging.
This has resulted in medical resource and financial burdens [1–3]. It has
been reported that 90.5 million cancer cases were diagnosed worldwide
in 2015, and more than 14 million patients are diagnosed with cancer
each year, with 2 million cancer-related deaths per year [4]. In recent
years, therapeutic methods such as surgical techniques, targeted drugs,
and radiochemotherapy have advanced considerably. However, the
prognosis of many cancers remains poor because of the lack of effective
early diagnostic methods and prognostic indicators [5]. Therefore, di-
agnostic and prognostic biomarkers must be identified.
Studies of protein-coding genes remain the focal point of cancer
pathogenesis research. However, protein coding regions account for
only 2 % of the human genome. More than 80 % of the eukaryotic
transcriptome contains non-coding RNAs, particularly long non-coding
RNAs (lncRNAs). lncRNAs are mRNA-like transcripts more than 200
nucleotides in length [6]. Many studies have shown that lncRNAs are
dysregulated in some cancers, regulate cancer pathways, and partici-
pate in cancer development [7,8]. Additionally, lncRNAs play im-
portant roles in stem cell differentiation, regulating pluripotency, and
tumorigenesis [9–11]. lncRNAs are up- or down-regulated during
[11]; these molecules have been identified as clinically useful diag-
nostic or prognostic biomarkers or therapeutic targets for cancer be-
cause of their high sensitivity and specificity [12].
The lncRNA SOX2 overlapping transcript (SOX2OT) is mapped to
human the chromosome 3q26.3 (Chr3q26.3) locus [13,14]. SOX2OT
produces at least 8 transcript variants and is highly expressed in em-
bryonic stem cells [13]. The gene is transcribed in the same orientation
as SOX2, an HMG-box transcription factor. SOX2 is embedded in the
intronic region of SOX2OT [15]. The SOX2OT gene is consists of 10
exons and more than two transcription start sites that exhibit compli-
cated transcriptional features. Some lncRNA transcript variants of the
human SOX2OT gene are related to cancer and stem cell-related path-
ways [16]. Recent studies demonstrated that SOX2OT is up- or down-
regulated in various cancer tissues and cell lines, affecting tumor pro-
gression. Here, we summarize recent findings related to SOX2OT ex-
pression, function, and regulation mechanisms in human cancer
(TABLE1,TABLE2).
2. SOX2OT in various cancers
2.1. Lung cancer
Lung cancer (LC) is the one of leading causes of cancer death

⁎
Corresponding authors at: Department of the Central Laboratory, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine,
Central South University, Changsha 410013, Hunan, People’s Republic of China.
E-mail addresses: wangying1171@163.com (Y. Wang), liaoqianjin@hnszlyy.com (Q. Liao), wangjing0081@hnszlyy.com (J. Wang).

https://doi.org/10.1016/j.biopha.2019.109725
Received 18 August 2019; Received in revised form 2 December 2019; Accepted 5 December 2019
0753-3322/ © 2019 Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/BY-NC-ND/4.0/).
Y. Wang, et al.
worldwide [17]. It has two major subtypes, small cell lung cancer and
non-small cell lung cancer (NSCLC). NSCLC accounts for approximately
85 % of lung cancer cases [18]. LC is one of the most aggressive ma-
lignant cancers, with a 5-year overall survival (OS) rate of approxi-
mately 15 %; each year, nearly 1.4 million people are diagnosed with
LC worldwide [19]. Thus, new biomarkers and therapeutic targets are
needed to facilitate early detection and improve patient survival. Hou
et al. [20] found that the expression level of SOX2OT in 53.01 % of
human primary LCs was 2-fold higher than that in pair-matched ad-
jacent non-tumor samples. Compared to in adenocarcinomas, SOX2OT
expression is significantly higher in squamous cell carcinoma of the
lung. Additionally, high SOX2OT expression is associated with the poor
survival of patients with LC. Functionally, knockdown of SOX2OT in-
hibited cell proliferation by decreasing the number of cells in S phase
and inducing G2/M arrest. The protein expression of EZH2 and cyclin
B1 and Cdc2 were reduced, and ectopic expression of EZH2 restored the
G2/M transition and cyclin B1 and Cdc2 protein expression. Similarly,
studies demonstrated that SOX2OT expression was obviously higher in
NSCLC tissues [21–23] and serum samples [21,22] than in normal
controls. Kamel et al. [22] demonstrated that SOX2OT expression was
upregulated in stage III and IV cancers. They distinguished patients
with NSCLC from controls using an area under area under the curve of
0.73 (sensitivity 76.3 % and specificity 78.6 %) for SOX2OT expression.
Marie et al. [23] reported that the expression of SOX2OT variants 4 and
7 was higher in NSCLC tumors than in normal tissues, particularly in
lung squamous cell carcinoma (SCC). Knockdown of SOX2OT reduced
the colony formation ability of cancer cells and induced the G2/M
phase of the cell cycle. Kaplan-Meier analysis demonstrated that high
expression of SOX2OT was associated with a low OS rate [20,21]. Teng
et al. [24] found that exosomal SOX2OT in patients with SCC was
significantly upregulated compared to that in negative control subjects.
Its area under the receiver operating characteristic curve was 0.815,
with a sensitivity and specificity of 76 % and 73.17 %. After surgery,
exosomal SOX2OT levels were reduced. SOX2OT expression is asso-
ciated with some clinical pathological parameters, such as tumor size,
lymph node metastasis, and TNM stages. Zhang et al. found that
knockdown of SOX2OT inhibited the proliferation, migration, invasion,
and epithelial-mesenchymal transition (EMT) process by binding to
miR-132, decreasing the expression of zinc finger E-box-binding
homeobox 2 (ZEB2), which was reversed by miR-132 inhibition [25].
Taken together, SOX2OT functions as a carcinogenic lncRNA and may
be a useful diagnostic and therapeutic target for lung cancer prognosis.
2.2. Gastric cancer
According the worldwide cancer statistics, gastric cancer (GC) is the
third leading cause of cancer mortality [26]. Despite a decrease in the
incidence of GC in the last few decades, 24,950 new GC cases were
diagnosed based on 2015 American cancer statistics [27]. The prog-
nosis of patients with GC remains low, and relapse occurs in more than
half of surgically treated cases [28]. To enable early diagnosis and ef-
fective targeted therapy, new biological markers must be identified.
Pourandokht et al. [29] evaluated GC tissues, paired adjacent normal
tissues, and GC cells and found that SOX2OT expression was decreased
in cancerous tissues. This expression was lower in high-grade than in
low-grade disease. Zou et al. [30] detected the expression of SOX2OT in
GC tissues and normal tissues and found that it was upregulated in
tumors and correlated with TNM stage, differentiation, and metastasis.
High SOX2OT expression was associated with poorer OS and disease-
free survival. They also found that SOX2OT expression was associated
with grade, T stage, distant metastasis, and differentiation. High
SOX2OT expression was correlated with poor OS and disease-free sur-
vival. Zhang et al. [31], Wei et al. [32], and Qu et al. [33] showed
similar results when SOX2OT was overexpressed in GC tissues and cell
lines. Studies of SOX2OT in GC have shown controversial results. Some
studies showed that SOX2OT acts as a suppressor, whereas others
2
Biomedicine & Pharmacotherapy 123 (2020) 109725
predicted its function as an oncogene. These contrasting results may be
related to the differential expression of SOX2OT variants in different
tissues [29–33]. GC cell growth and motility were inhibited by down-
regulation of SOX2OT expression [31]. Wei et al. [32] reported that
SOX2OT can oppositely regulate the expression of miR-1945p via EMT,
whereas knockdown of SOX2OT inhibited cell proliferation, invasion,
and migration and matrix metalloproteinase (MMP)-2 and MMP9 ex-
pression in GC cells. Qu et al. [33] revealed that overexpression of
SOX2OT promoted cell proliferation and metastasis by decreasing the
expression of miR-194-5p from AKT2. SOX2OT may also play an im-
portant role in diagnosis and therapy.
2.3. Esophageal cancer
Esophageal cancer (EC) shows one of the highest incidence rates and
death rates from cancer worldwide, and esophageal squamous cell
carcinoma (ESCC) is one of the main pathological types in Asian
countries [34]. Many studies have revealed the pathogenesis of eso-
phageal adenocarcinoma, but the ESCC does not have a clear origin
[35]. Most patients with EC are diagnosed in the middle or late stage
when therapeutic strategies are no longer effective [36]. Aliereza et al.
[14] demonstrated that SOX2OT is present in the nucleus and is highly
expressed along with SOX2 and OCT4 in ESCC tissues and cells. They
also found that knockdown of the two variants, SOX2OT-S1 and
SOX2OT-S2, altered the distribution of cells in the G1 and sub-G1
phases, whereas only SOX2OT-S1 suppression decreased SOX2 expres-
sion. This study suggested that variants of SOX2OT play a vital role in
tumor progression and maintenance of the pluripotent state. Tian et al.
[37] analyzed the expression of lncRNAs, miRNAs, and mRNAs in The
Cancer Genome Atlas and found that high expression of SOX2OT was
significantly associated with poor prognosis. Wu et al. [38] showed that
SOX2OT was up-regulated in ESCC tissues and cells. They found that
overexpression of SOX2OT promotes ESCC cell growth in the presence
of cisplatin and that ectopic expression of SOX2OT promotes the pro-
liferation of ESCC cells. These studies suggested that SOX2OT is in-
volved in ESCC tumor initiation and/or progression and therapy.
2.4. Breast cancer
Breast cancer has one of the highest incident rates among malignant
tumors and shows a very high mortality rate [26]. The evolution and
improvement of traditional treatments have substantially increased the
5-year survival rate [39]. Breast cancer is a molecularly heterogeneous
disease. Effective biomarkers are necessary to predict outcomes and
determine the best treatment. Mostafa et al. [40] analyzed the expres-
sion of SOX2OT and found that it is overexpressed in breast cancer
tissues vs their adjacent noncancerous tissues. However, no association
between SOX2OT and clinical data was observed. Marjan et al. [41]
examined the expression of SOX2OT in estrogen receptor-positive (ER
+) and estrogen receptor negative (ER-) breast cancer samples. They
found that SOX2OT expression was higher in ER + than in ER- tumors
and cell lines. Its overexpression can increase anchorage-independent
cell growth and delay cell cycle progression. Tang et al. [42] confirmed
that SOX2OT was overexpressed in breast tissues and that its high ex-
pression was significantly associated with the T allele of rs9839776.
These studies suggest that SOX2OT is a valuable diagnostic and ther-
apeutic biomarker for breast cancer.
2.5. Hepatocellular carcinoma
Hepatocellular carcinoma (HCC) is a malignant tumor with a high
incidence, particularly in China [43]. The mortality rate of HCC ranks
second among all malignant tumors. Because this disease is difficult to
treat by surgery, shows a high recurrence rate, and lacks effective
therapies after recurrence, treatments for HCC must be improved [44].
The molecular mechanism of these malignant tumors should be
Y. Wang, et al.
evaluated in greater detail. Sun et al. [45] and Shi et al. [46] demon-
strated that the expression of SOX2OT was upregulated in HCC tissues
compared to in non-tumor tissues, which was associated with poor
prognosis. High expression of SOX2OT is associated with tumor size,
tumor number, and vein invasion rate. Shi et al. [46] demonstrated that
high expression of SOX2OT was correlated with histological grade,
TNM stage, and vein invasion. Patients showing higher expression of
SOX2OT had a poorer prognosis [45,46]. SOX2OT plays crucial roles in
cell invasion and cell migration of HCC. Sun et al. [45] also found that
this protein can promote the EMT of MHCC97H and SMCC-7721 cells.
Therefore, SOX2OT shows potential as a biomarker and therapeutic
target for patients with HCC.
2.6. Ovarian cancer
Ovarian cancer (OC) has among the highest morbidity and mortality
rates among gynecological malignancies. More than 80 % of patients
with OC have epithelial ovarian cancer, and most cases are serous.
Although treatment options, surgery, and chemotherapy have im-
proved, the 5-year survival rate remains at approximately 30 %. This is
mostly because 70 % of patients are diagnosed at an advanced stage
[27]. To develop effective methods for the early prevention, diagnosis,
and treatment of OC, studies are needed to further understand the
molecular mechanism of the complex biological processes involved.
Han et al. [47] reported that SOX2OT was upregulated in OC tissues
and cells, and high expression of SOX2OT was negatively correlated
with prognosis. Knockdown of SOX2OT inhibited cell colony formation
capacity, migration, and cell invasion, arrested the cell cycle, decreased
the expression of the mesenchymal protein N-cadherin, and increased
expression of the epithelial protein E-cadherin. Therefore, SOX2OT may
be a useful therapeutic target in ovarian cancer treatment.
2.7. Pancreatic ductal adenocarcinoma
Pancreatic ductal adenocarcinoma (PDAC) shows among the
poorest prognoses of cancers worldwide. The median survival time is
very low at approximately 6 months, with a 5-year survival rate of only
3 % [26]. Because the pathophysiological mechanisms are unknown, no
suitable therapies are available. Li et al. [48] found that the plasma
exosomal expression of SOX2OT in PDAC was upregulated and asso-
ciated with TNM stage. Patients expressing low levels of SOX2OT
showed a longer survival time than those with high SOX2OT expres-
sion. They also found that SOX2OT regulates the expression of SOX2 by
binding to miR-200 family members, which promote EMT, cell inva-
sion, and metastasis. Zhang et al. [49] also observed overexpression of
SOX2OT in PDAC. These studies suggest that SOX2OT is a valuable
biomarker and therapeutic target for PDAC.
2.8. Cholangiocarcinoma
Cholangiocarcinoma is a malignant neoplasm originating from
epithelial cells within the liver or biliary tract [50]. In recent years, the
incidence of CCA has increased. Most patients with CCA are diagnosed
at advanced stages. Surgery, chemotherapy, and radiotherapy are the
main therapy methods. Patients who are in the early stage typically
undergo radical resection, resulting in an average overall survival time
of longer than 12 months; in the absence of radical resection, the sur-
vival time is very short [51]. Chemotherapy and radiotherapy are not
effective in patients in advanced stages. The 5-year survival rates of
patients with CCA is up to 35 % [52]. Thus, novel diagnostic and
prognostic biomarkers or therapeutic targets for CCA are needed [53].
Li et al. [54] and Wei et al. [55] found that SOX2OT was highly ex-
pressed in cholangiocarcinoma tissues, and patients showing high ex-
pression of SOX2OT had a shorter OS. When the expression of SOX2OT
was knocked down, cell proliferation and metastasis were inhibited. Li
et al. [54] reported that overexpression of SOX2OT was correlated with
3
Biomedicine & Pharmacotherapy 123 (2020) 109725
lymph node invasion, TNM stage, and postoperative recurrence. Wei
et al. [55] also investigated the mechanism by which the transcription
factor IRF4 promotes the transcriptional activity of SOX2OT and then
upregulates SOX2OT. SOX2OT can upregulate SOX2 and PTEN by ac-
tivating PI3K/AKT signaling. Therefore, SOX2OT may be a useful bio-
marker and therapeutic target in CCA.
2.9. Osteosarcoma
Osteosarcoma is among the most common skeletal tumors in chil-
dren and adolescents [26]. Osteosarcoma originates from the malignant
transformation of mesenchymal cells and shows a high mortality rate
[56]. The 5-year survival rate of patients with osteosarcoma is 5–20 %
[57]. Advances in surgery and chemotherapy have improved the sur-
vival of osteosarcomas patients but the survival rate remains un-
satisfactory. Thus, new biomarkers and therapy targets must be iden-
tified. Wang et al. [58] measured the expression of SOX2OT and
evaluated its biological function in osteosarcoma. They found that
SOX2OT is an oncogene in osteosarcoma and that its high expression is
associated with poor prognosis. SOX2OT can regulate osteosarcoma cell
proliferation, migration, and invasion as well as the expression of some
cancer stem cell biomarkers. Wang et al. [59] found that SOX2OT
variant 7 plays an important role in the effect of epigallocatechin gal-
late on reducing doxorubicin-induced autophagy.
2.10. Other cancers
Some recent studies reported that SOX2OT has an oncogene role in
some other cancers, such as laryngeal squamous cell carcinoma (LSCC),
nasopharyngeal carcinoma (NPC), and glioblastoma.
Tai et al. [60] reported that SOX2OT was upregulated in LSCC tis-
sues and negatively correlated with PTEN expression. In LSCC cells,
overexpression of SOX2OT may promote cell proliferation, migration,
and invasion and suppress apoptosis. PTEN expression can be inhibited
by the binding of SOX2OT to EZH2. PTEN overexpression and EZH2
silencing can abrogate SOX2OT overexpression-mediated LSCC cell
malignant activity. Feng et al. [61] also demonstrated that SOX2OT was
increased in LSCC tissues compared to in adjacent non-neoplastic tis-
sues by microarray analysis. Zhang et al. [62] reported that the ex-
pression of the SOX2OT was high in NPC tissues and cells and asso-
ciated with TNM stage, distant metastasis, and poor clinical prognosis.
They found SOX2OT can bind to miR-146b-5p to regulate the expres-
sion of HNRNPA2B1, which regulates NPC progression. Su et al. [63]
reported that SOX2OT was overexpressed in glioma tissues and stem
cells (GSCs), and that high SOX2OT expression can promote the cell
proliferation, migration, and invasion of GSCs, inhibiting apoptosis.
These data suggest that SOX2OT is a valuable biomarker and ther-
apeutic target for LSCC, NPC, and glioblastoma.
3. Regulatory mechanisms of SOX2OT in human cancers
SOX2OT is overexpressed in many cancers and plays important role
as an oncogene by promoting cell proliferation, invasion, migration,
and growth and suppressing cell apoptosis (Table 1). The mechanism of
SOX2OT mediation is complex and involves many factors (Fig. 1).
3.1. Regulation of SOX2 expression
SOX2 is a transcription factor that plays a critical role in estab-
lishing and maintaining the pluripotency of cancer stem cells. Because
the SOX2 gene is embedded in the intronic region of SOX2OT, SOX2OT
can regulate SOX2 expression to affect osteosarcoma cell migration and
invasion as well as the expression of some cancer stem cell biomarkers
such as OCT4, NANOG, ALDH1, CD44, and CD133 [58]. Studies de-
monstrated that SOX2OT regulates the expression of SOX2 to promote
the proliferation, invasion, and migration and decrease cell apoptosis of
Y. Wang, et al. Biomedicine & Pharmacotherapy 123 (2020) 109725

various cancer cells such as in ESCC [14], breast cancer [41], PDAC
References

[31–33]

[40–42]

[63–65]
[20,25]

[45,46]
[48,49]

[54,55]
[58,59]
[48], osteosarcoma [58], and cholangiocarcinoma [55]. Although the

[29]

[47]

[58]

[62]

[66]
mechanism is unknown, Li et al. [48] suggested that SOX2OT binds to
miR-200 family members to regulate SOX2 expression (Table 2).
EZH2, Cyclin B1, Cdc2, miR-132, ZEB2, N-cadherin, vimentin and E-cadherin

miR-194-5p, miR-122, SOX3, TDGF-1, JAK/STAT, NSPc1, CDK2, CDK2AP2,

3.2. Suppressor of EMT

EMT is associated with tumor invasion and metastasis [68]. When

EMT occurs, its associated proteins such as N-cadherin, vimentin, Snail,
Slug, Twist, and Zeb1/2 as well as MMP are up-regulated, whereas E-
cadherin is down-regulated [69]. In studies of GC, OC, lung cancer, and
HCC, knockdown of SOX2OT resulted in down-regulation of MMP‑2,
MMP‑9, Twist1, vimentin, and N‑cadherin and up-regulation of E‑cad-
N‑cadherin, cyclin B1, Cdc25C and E‑cadherin

herin [25,32,45,47]. These data illustrate that EMT is suppressed by

SOX2OT.

miR‐211, MCL‐1 isoform2, Akt/mTOR/

miR‑194‑5p,MMP‑2, MMP‑9 and AKT2

ACTR3, SMC4, INCENP and GNL3L

Twist1, E‑cadherin and N‑cadherin

3.3. Activation of AKT signaling pathway and inhibition of the JAK/STAT

SOX2, OCT4, NANOG, ALDH1,
IRF4, SOX2, PTEN, PI3K/AKT

signaling pathway
Sox2, miR-200, YY1, Sox2

Wei et al. [55] demonstrated that SOX2OT inhibits PTEN tran-

scription, followed by activation of the PI3K/AKT signaling pathway.
CD44 and CD133

p70S6K pathway

Yin et al. [66] found that SOX2OT activates the AKT/mTOR/p70S6K

miR‐146b‐5p/
Related genes

HNRNPA2B1
EZH2, PTEN

pathway by targeting the miR-211/MCL-1 isoform 2 axis. Su et al. [64]

found that SOX2OT binds to miR-194-p and miR-122 regulates the
mRNA and protein expression of SOX3 and TDGF-1, as well as inhibits
–
–

the JAK/STAT signaling pathway.

Proliferation, cell cycle, migration, invasion, and (EMT)

Invasion and metastasis, cells growth and Proliferation

3.4. Acting as competing endogenous RNA (ceRNA)

Cells growth, proliferation, migration, invasion, and

Cell proliferation, arrested cell cycle, facilitated cell

Studies demonstrated that SOX2OT act as a competing endogenous

Proliferation, anchorage-independent growth

Proliferation, migration, invasion, apoptosis

RNA (ceRNA) to inhibit cell proliferation, invasion, and migration

which involves related genes, such as ZEB2, by regulating miR-132
proliferation, migration and invasion

[25]. Zhang et al. [62] demonstrated that SOX2OT regulates the NPC
invasion, apoptosis and autophagy
Proliferation, migration, invasion
process, colony formation ability

cell migratory and invasive capacities via sponging miR-146-5p and

Cell proliferation and metastasis
Cell proliferation and motility

modulating HNRNPA2B1. Su et al. [63] revealed that SOX2OT knock-

Cell migration and invasion

apoptosis, and metastasis

down increased miR-194-5p and miR-122 expression, down-regulated

Cell viability, migration,

SOX3 expression, and decreased TDGF-1 expression and inhibited the

Biological function

JAK/STAT signaling pathway. This inhibited the proliferation, migra-

tion, and invasion of GSCs, as well as promoted the apoptosis of GSCs.
Yin et al. [66] found that knockdown SOX2OT regulated miR-211,
metastasis

MCL-1 isoform 2, and the Akt/mTOR/p70S6K pathway and protected

pheochromocytoma (PC‐12) cells from H2O2-induced injury. However,
–

whether these effects are direct or indirect remains unknown.

Tumor suppressor

3.5. Other mechanisms

Oncogene

Oncogene

Oncogene

Oncogene
Oncogene
Oncogene
Oncogene
Oncogene
Oncogene

Oncogene

Oncogene

Tai et al. [60] found that SOX2OT can recruit enhancer of zeste
Role

homolog 2 (EZH2) to promote H3K27me3 and negatively regulate

–
Functional characterization of SOX2OT in various cancers.

PTEN expression. SOX2OT regulates carcinogenesis, metastasis, and

Down-regulated

apoptosis-related genes such as EZH2, cyclin B1, and Cdc2 [20] as well
Up-regulated

Up-regulated

Up-regulated

Up-regulated
Up-regulated
Up-regulated
Up-regulated
Up-regulated
Up-regulated

Up-regulated

Up-regulated
Expression

as metastasis-related genes such as MMP-2 and MMP-9 [32]. Marie

et al. [65] showed that knockdown of SOX2OT regulates cell pro-
liferation-related gene expression and developmental processes. Parti-
–

cularly, SOX2OT regulates some cell cycle and mitotic regulatory genes,
such as CDK2, CDK2AP2, and ACTR3, and chromosome structure-as-
Esophageal squamous cell carcinoma

sociated genes, such as SMC4, INCENP, and GNL3L. Wang et al. [63]
Laryngeal Squamous Cell Carcinoma
Pancreatic ductal adenocarcinoma

suggested that SOX2OT binds and cross-talks with the NSPc1 polycomb
protein complex in glioma H4 cells to regulate cell growth and apop-
Nasopharyngeal carcinoma

tosis. SOX2OT was also found to be hypomethylated in patients with

Hepatocellular carcinoma

smoking-related and HPV + head and neck SCC [70]. The transcription
Cholangiocarcinoma

Pheochromocytoma

regulators Yin Yang-1 and IRF4 act as upstream transcription factors of

Ovarian cancer

SOX2OT in PDAC [49] and cholangiocarcinoma [58].

Gastric cancer

Gastric cancer

Osteosarcoma

Glioblastoma
Lung cancer
Cancer type

(ESCC)

4. Conclusions and future perspectives

Table 1

SOX2OT has been widely studied in various human cancers.

4
Y. Wang, et al. Biomedicine & Pharmacotherapy 123 (2020) 109725

Fig. 1. Regulatory mechanisms of SOX2OT in human cancers.

Table 2
Clinical significance of SOX2OT in various cancers.
Cancer type Clinicopathological features References

Lung cancer Histological type, Smoking status, tumor size, lymphatic metastasis, pTNM stage, shorter overall survival [20–25,67]
Gastric cancer Malignant status, T stage, distant metastasis and differentiation, and poor prognosis [29–33]
Esophageal squamous TNM stage and poor prognosis [37]
cell carcinoma
Ovarian cancer Age, tumor size, TNM stage, lymphatic metastasis, [47]
Hepatocellular carcinoma increased tumor size, tumor number, and vein invasion rate, poor prognosis, advanced histologic grade, higher TNM stage, and [45,46]
positive vein invasion
Pancreatic ductal adenocarcinoma TNM stage, lymphatic or [48,49]
vascular invasion, and overall survival
Cholangiocarcinoma Lymph node [54,55]
invasion, TNM stage and poor prognosis
Osteosarcoma Enneking stage, tumor size, distant metastasis, histological grade, and poor prognosis [58]
Nasopharyngeal carcinoma TNM stage, distant metastasis, and poor prognosis [62]

SOX2OT is upregulated in different types of tumors and plays an on-
cogenic role in most cancers, such as LC, ESCC, breast cancer, OC, HCC,
PDAC, LSCC, cholangiocarcinoma, osteosarcoma, NPC, and glio-
blastoma. However, the expression of SOX2OT is controversial in GC.
The regulatory mechanisms of SOX2OT are complex and involve mul-
tiple factors, including regulation of SOX2, suppression of EMT pro-
gression, activation of the AKT signaling pathway, inhibition of the
JAK/STAT signaling pathway, functioning as a ceRNA, and effects on
carcinogenesis. However, the precise mechanism of its upstream reg-
ulation and downstream signaling must be systematically investigated
and confirmed.
Dysregulation of SOX2OT is associated with malignant clin-
icopathological characteristics and poor prognosis, suggesting its po-
tential function in tumor diagnosis and prognosis prediction. However,
the expression and chemical stability of SOX2OT in body fluids remains
unclear. To become a viable diagnostic and prognostic biomarker, ad-
ditional studies of SOX2OT are needed, particularly in larger cohorts.
Understanding its specific functions and mechanisms may lead to the
clinical application of SOX2OT. Although many studies have been
conducted, some questions remain. For example, do triggers exist that
alter SOX2OT? Do the different transcripts of SOX2OT have distinct
functions? To clarify the molecular mechanisms of SOX2OT, its role
should be examined in various diseases to provide a foundation for
studies of SOX2OT and clinical applications.
Funding sources
This work was supported by grants from the National Natural
Scientific Foundation of China [grant number 81603207] and Hunan
Clinical Research Center In Gynecologic Cancer and Hunan Provincial
Natural Science Foundation-Science and Health Joint Project [grant
numbers 2017JJ3189, 2018JJ3318, 2018JJ6027].
Declaration of Competing Interest
The authors declare that there are no conflicts of interest.
Acknowledgements
We would like to thank Editage (www.editage.cn) for English lan-
guage editing.
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