Discussion
Recent evidence has shown that 98% of the human genome could be
transcribed into non-coding RNAs (Tao et
al., 2015). A large body of studies emphasizes the potential functional
roles of lncRNAs in various biological mechanisms and tumorigenesis
(Yan et al., 2017,
Kong et al., 2016). Altered and aberrant
expression of lncRNAs in numerous tumor samples has been well
documented, which drives several putative carcinogenesis mechanisms
(Li et al., 2018a,
Li et al., 2018c,
Yan et al., 2017). The lncRNA GAS5plays a vital role as a tumor suppressor lncRNA in almost all cancers
(Zheng et al., 2016,
Li et al., 2017,
Li et al., 2018c,
Guo et al., 2017). LncRNA GAS5also encodes small nucleolar RNAs (snoRNAs) and acts as a glucocorticoid
riborepressor. Previous investigations have shown that GAS5overexpression inhibits osteosarcoma’s tumorigenesis and
epithelial-mesenchymal transition (EMT) by regulating the miR-221/ARHI
pathway (Smith and Steitz, 1998,
Xu et al., 2018). There is substantial
literature reporting clinical cancer therapy approaches for lncRNAGAS5 . Several reports have shown a down-regulation of GAS5in various cancer cells, associated with a poorer prognosis
(Cao et al., 2014,
Kong et al., 2016,
Mourtada-Maarabouni et al., 2009,
Li et al., 2018a). Whereas it has been
demonstrated the upregulation of GAS5 is associated with a more
promising outcome in prostate cancer therapy
(Yan et al., 2017). It has been
demonstrated that GAS5 can inhibit cell growth by spongingmiR-21, which results in the upregulation of phosphatase
and tensin homologs (PTEN ) and inhibition of the mTOR signaling
pathway in trastuzumab-resistant HER2-positive breast cancer
(Oldoni et al., 2016). Furthermore, the
downregulation of lncRNA GAS5 confers tamoxifen resistance by
activating miR-222, which targets PTEN in breast cancer
(Gu et al., 2018).
The underlying mechanisms of lncRNA GAS5 are not fully
understood. Numerous investigations have reported that polymorphisms in
lncRNA might have a crucial impact on the lncRNA functions
(Kong et al., 2016). Current evidence has
shown that lncRNA GAS5 rs145204276 polymorphism could predispose
patients to cancer. However, the results concerning the association of
the lncRNA GAS5 rs145204276 polymorphism and cancer risk have
been inconsistent (Li et al., 2018c,
Li et al., 2017,
Tao et al., 2015,
Xu et al., 2018,
Yuan et al., 2018,
Zheng et al., 2016,
Zhu et al., 2017,
Zhu et al., 2016). For instance, Zhuet al. showed that the del allele elevated colorectal cancer risk
in the patients (Zhu et al., 2016). At
the same time, Zheng et al. found that the del allele was
significantly associated with decreased colorectal cancer risk
(Zheng et al., 2016). In addition,
previous studies have indicated that the lncRNA GAS5 rs145204276
polymorphism could reduce the risk of gastric cancer
(Aminian et al., 2019,
Li et al., 2018b). Different factors,
including variation in populations and ethnicity, different cancer types
or lack of statistical power, could cause this discrepancy. Therefore,
we conducted this meta-analysis by ten eligible studies, including 6917
cases and 8977 controls, to increase the strength of assessing the
association of the lncRNA GAS5 rs145204276 polymorphism and
cancer risk. To the best of our knowledge, this meta-analysis is the
first meta-analysis which systematically considers all eligible studies
in the association of the lncRNA GAS5 rs145204276 polymorphism
with cancer risk. In this study, we did not find any significant
association between the lncRNA GAS5 rs145204276 polymorphism with
cancer risk in the different genetic models. Interestingly, in subgroup
analysis based on cancer types, we found that the polymorphism was
associated with decreased gastric cancer risk in the patients. It has
been demonstrated that the lncRNA GAS5 rs145204276 del allele
positively correlated to P27Kip1 expression in gastric
cancer patients (Aminian et al., 2019).
Besides, P27Kip1 has been shown to act as a tumor
suppressor gene, and its down regulation has been reported in various
cancers (Ogino et al., 2009,
Zhuang et al., 2011).
However, in subgroup analysis based on the source of control, the data
did not show a significant association between the polymorphism and
cancer risk. Sensitivity analyses revealed that the results were stable
and robust among the different genetic models. No publication bias was
found in the meta-analysis. In fact, it indicates that our meta-analysis
is reliable. However, this meta-analysis has some limitations. These
limitations may be a guide for future studies to overcome them. First,
only studies written in English were included. Second, the subgroup
analysis was limited to cancer types and sources of control. We did not
consider an analysis of other variables such as lifestyle factors (e.g.,
smoking, exercise, and alcohol consumption), environmental factors,
gender, stage of cancer, metastasis, and chemotherapy response due to
inadequate and inaccessible data of the eligible articles. Third, the
sample sizes of the studies were relatively small, which could have a
dramatic impact on the power of the study. Fourth, there was
heterogeneity in our pooled results which may originate from different
types of cancers. All of the included population samples were from
China. Finally, genotyping errors may be possible due to applying other
genotyping methods. Hence, it is necessary to conduct further studies in
different ethnicities with large sample sizes and consider more
comprehensive criteria for assessing lncRNA GAS5 and cancer
risks.