Nasopharyngeal carcinoma (NPC) is an aggressive epithelial carcinoma that is prevalent
in Southeast Asia, Southern China and North Africa. It can develop in the presence
of various risk factors, including Epstein-Barr virus (EBV) infection, environmental
exposure to carcinogens, ethnic background, and genetic predisposition. It is prone
to local invasion and early distant metastasis. Patients with early-stage NPC have
a relatively high cure rate of over 90% with radical radiotherapy. In contrast, the
5-year overall survival (OS) rate for locally advanced NPC declines to between 50–60%
(1). With the combination of intensity-modulated radiotherapy, chemotherapy, surgery
and targeted therapy, the locoregional control rate has been reported to be 80–90%
in locally advanced NPC, whereas distant metastasis remains the major reason of treatment
failure in these patients (2-4). The outcome for patients with distant metastatic
NPC is suboptimal, with a median OS of 20 months (5). Unfortunately, roughly 15% NPC
patients present with distant metastases at their first diagnosis (6). The understanding
of the mechanisms that drive NPC metastasis will be substantially beneficial for developing
new and reliable biomarkers for early detection and novel therapeutic strategies for
NPC.
The specific molecular mechanisms that drive NPC metastasis remain unclear. The most
common histologic type in Eastern countries is undifferentiated carcinoma, while squamous
cell carcinoma is more common in USA and Europe. Undifferentiated carcinoma is strongly
associated with EBV infection. EBV encodes the oncogene product, latent membrane protein
1 (LMP1). LMP1 executes its oncogenic functions via activating the P38 MAPK signaling
pathway, and subsequently decreasing the sensitivity of NPC cells to ionizing radiation
(7). Moreover, LMP1-mediated metabolic reprogramming activates IGF1-mTORC2 signaling
pathway, facilitates PDHE1α nuclear translocation that leads to acetylation and activation
of the Snail promoter (8). However, no efficient EBV targeted therapy has been developed
in NPC treatment. Intriguingly, noncoding RNAs, including microRNAs and long noncoding
RNAs, are increasingly implicated and appreciated as playing critical roles in the
mediation of NPC metastasis (9-12).
In this Journal, Lin et al. reported an association between Tetraspanin 8 (TSPAN8)
and distant metastasis of NPC (13). There was 1,787 differential expressed genes between
paired tumor tissues and benign adjacent tissues from NPC with 8 genes that were highly
upregulated in NPC tissues. However, only TSPAN8 is over-expressed in the poorly differentiated
CNE2 cell line and the highly metastatic subclone S18 NPC cell line. More importantly,
TSPAN8 promotes invasion and migration in NPC cell lines in vitro. When TSPAN8 is
silenced in poorly differentiated CNE2 cells, it leads to the down-regulation of pro-inflammatory
factor IL-1β, which inhibits the AKT/MAPK pathway and attenuates metastasis. The authors
further explored whether TSPAN8 could predict the prognosis of NPC. Immunohistochemistry
experiments indicated that increased TSPAN8 level in NPC was linked to short OS and
metastasis-free survival, suggesting that TSPAN8 could be utilized as a prognostic
biomarker for NPC patients (13). This is the first report to suggest that TSPAN8 plays
a critical role in the progression and metastasis of NPC.
The TSPAN8 gene encodes for a cell surface glycoprotein that is a member of the 4-transmembrane
protein family. It was originally found to be expressed in several types of cancers
but not in most normal tissues (14). Subsequently, it was found to be involved in
the progression of pancreatic cancer (15), breast cancer (16), lung cancer (17), melanoma
(18,19), gastric cancer (20) and hepatocellular cancer (21). It was also discovered
that β-catenin stabilization is a molecular response after the onset of TSPAN8 activation
in melanoma, that suggests that β-catenin and TSPAN8 are part of a positive feedback
loop and sustains a high TSPAN8 expression level (19). The knockout of TSPAN8 down-regulates
WNT pathway activity, reduces β-catenin expression and subsequent translocation to
the nucleus in gastric cancer (22). The effect of TSPAN8 on β-catenin is mediated
by the binding to NOTCH2 (22). In addition, TSPAN8 promotes gastric cancer cell growth
and metastasis at least partially through the activation of ERK-MAPK pathway (23).
Furthermore, it has been shown that TSPAN8 and its regulators control early melanoma
invasion. This indicates that TSPAN8 is a promising novel therapeutic target by regulating
downstream of the RAF-MEK-ERK signaling pathway (18). However, it is unknown if the
function of TSPAN8 in NPC is associated with EBV virus status. This topic remains
one of interest given the prevalence of EBV infection in patients with NPC. Notably,
the authors of this study have demonstrated that TSPAN8 may play a role in tumor progression
and metastasis through AKT/MAPK pathway in NPC, which implicates a new mechanism of
TSPAN8 in regulating cancer cells.
Interestingly, the role of TSPAN8 in promoting cancer stemness has been highlighted
recently (16,24,25). Cancer stem cells (CSCs) are a small cell population within the
tumor microenvironment (TME). Emerging evidence has suggested that CSCs serve as the
basis of cancer metastasis, solid tumor progression, and therapeutic resistance. TSPAN8
has been used as a marker of CSCs and was found to promote cancer stemness through
regulating stemness genes: NANOG, OCT4, and ALDHA1 (16,24). It is also an important
exosome component to mediate crosstalk between CSCs and their neighboring cells (25).
Furthermore, the expression of TSPAN8 is upregulated in breast CSCs and enhances stemness
maintenance through the activation of Hedgehog signaling (16). Therefore, it is suggested
that TSPAN8 is a potential therapeutic target to overcome treatment resistance contributed
by CSCs. It remains undecided that TSPAN8 contributes to distant metastasis and treatment
failure in NPC by functioning as CSC stemness guide. It would be worthy to further
explore this in order to develop effective therapeutic target to control distant metastasis.
Collectively, this study has shown that TSPAN8 promotes NPC progression and metastasis
through AKT/MAPK pathway. TSPAN8 is a potential biomarker for predicting metastasis
and prognosis of NPC patients, as well as a therapeutic target for NPC treatment.