Background
Hepatocellular carcinoma (HCC) represents the fifth most common cancer type and causes more than 500,000 cancer-related deaths every year worldwide [
1‐
3]. Although the majority of HCC cases develop in Asia, cases in China account for more than half of initially diagnosed HCC patients all over the world, and the city of Qidong in East China is one of the most highly endemic areas for HCC [
4,
5]. The etiology of HCC is diverse and complicated; hepatitis B (HBV) and hepatitis C (HCV) viral infections as well as liver cirrhosis often contribute to HCC development [
6,
7]. Despite substantial improvements in HCC management, including surgical resection, microwave ablation, liver transplantation, radiofrequency and chemotherapy, over the last 10 years, the prognosis of HCC remains unsatisfactory; moreover, the 5-year overall survival rate is less than 30% [
8,
9]. For now, alpha-fetoprotein (AFP) is still the most widely acknowledged marker in early detection and follow-up surveillance for HCC [
10]. However, because of the number of AFP negative HCC patients and the inadequate understanding of the molecular mechanism of HCC tumorigenesis, studies focusing on the novel biomarkers that are involved in the carcinogenic process of HCC development and correlated with malignant characteristics of HCC are urgently needed [
11].
SESN2, is transcriptionally regulated by p53, and belongs to the evolutionarily conserved sestrin family [
12]. As a critical downstream effector of p53, SESN2 could be induced in a p53-dependent manner, such as with DNA damaging treatments, or in a p53-independent manner, including hypoxia or oxidative stress [
12,
13]. SESN2 is involved in the regulation of cell survival, protection, and regeneration [
14,
15]. Moreover, SESN2 acts as an important contributor in autophagy induction and tumor suppression [
16,
17]. For example, SESN2 expression could be increased via the c-Jun N-terminal kinase (JNK) pathway to influence autophagy induction in cancer cells [
9,
18]. Several gene expression analyses have also shown down-regulated SESN2 expression in different types of lung cancers [
19,
20]. In addition, SESN2 expression inhibits cancer growth while increasing the sensitivity of cancer cells to ionizing radiation [
15,
21]. The upregulation of SESN2 can also induce apoptosis through the p53 signaling pathway [
22]. These studies suggest that SESN2 acts as a multi-functional molecule and is critically associated with tumor development. Nevertheless, the characteristics of SESN2 expression in HCC have been barely investigated.
To explore SESN2 expression in this study, we first detected the SESN2 expression using one-step quantitative-polymerase chain reaction (qPCR) test and Western blotting analysis in 15 fresh HCC tissues. Subsequently, we performed immunohistochemistry (IHC) analysis in a tissue microarray (TMA) containing 100 HCC tissue samples. Then, we analyzed the correlations of SESN2 expression with important clinicopathological characteristics of HCC patients. Finally we evaluated the prognostic role of SESN2 expression for HCC.
Discussion
Sestrins are a family of highly conserved, stress-inducible genes that can protect cells against oxidative damage and oncogenic signaling [
28]. Recently, one member of this family, SESN2, has received attention for acting as a tumor suppressor that can inhibit angiogenesis and promote apoptosis [
12,
29]. This finding underscores the significance of illustrating the molecular mechanism by which SESN2 affects pathways for metabolism and survival. Sanli et al. reported that SESN2 could facilitate AMPK phosphorylation through a combination effect with a tumor suppressor, LKB1 [
30] and increase enzyme auto-phosphorylation in breast cancer [
21]. SESN2 expression inhibited cell growth and proliferation by suppressing mTOR through AMPK signaling modulation [
15]. High expression of SESN2 was found to induce apoptosis through the AMPK/p38 signaling pathway in colon cancer cells [
31]. The induction of SESN2 also enhanced the oxidative stress response and showed protective effectiveness in mice against tumor development through mTOR, and p53/p21-signaling network [
32]. The above-mentioned information indicates that SESN2 has anti-oncogenic roles in several human cancers. The detailed relationship between SESN2 expression and clinicopathological significance of HCC deserve further exploration.
In the present study, the qPCR test indicated that the mRNA expression of SESN2 was critically reduced in HCC tissues compared with that in the corresponding noncancerous tissues. Moreover, the results of Western blotting and IHC analyses also demonstrated reduced protein expression of SESN2 in HCC cells relative to noncancerous cells. The above data are consistent with previous studies reporting the inhibited expression of SESN2 in several human cancers [
19,
20]. Moreover, considerable associations of SESN2 expression and crucial clinicpathological characteristics in HCC exist, including HBV and HCV infection. We found that high SENS2 expression indicated negative lymph node metastasis. Wei et al. also described that low SESN2 expression is correlated with positive lymph node metastasis in colorectal cancer [
33]. Our results agree with those obtained by Wei et al.; SESN2 expression could contribute to the restraint of certain malignant activities in HCC, such as tumor metastasis.
Thus far, studies concerning the association between SESN2 and cancer mortality in clinical samples are rare. In our present research, univariate and multivariate analyses illustrated that SESN2 expression and TNM stage were both correlated with the life span of HCC patients. In addition, the Kaplan-Meier curve analogously proved that HCC patients with low SESN2 expression encountered poor prognosis. The survival results were also in line with those of earlier studies, where high SESN2 expression prohibits tumor development and predicts favorable prognosis in cancers [
15,
22,
33]. In all, SESN2 exerts significant anti-oncogenic effects, and high SESN2 expression substantially suspends malignant behavior that facilitates tumor development.
There are some limitations in this study that I need to address. For one thing, we failed to collect some important clinical items for HCC patients, including their AFP values, portal vein invasion statuses and tumor differentiation statuses, which are considered significant elements of the HCC etiology and development. We will perform more comprehensive data collection in our future studies. For another, the application of archived HCC samples may increase the bias in this retrospective observational study. Future studies that enroll more participants are needed to validate the present findings. Finally, the potential manner by which SESN2 influences the tumor microenvironment in HCC has not yet been explored. Future studies are of great importance to explore the mechanism by which SESN2 plays a role in HCC development.
In conclusion, this study first reported the differential expression of SESN2 in HCC. In particular, decreased SESN2 expression was observed in HCC. SESN2 expression was significantly associated with certain malignant behavior of HCC, including HBV/HCV infection and lymph node metastasis. Thus, high SESN2 expression implicated advantageous prognosis in HCC patients. Our current research is valuable in exploring the characteristics of SESN2 in HCC development.
Conclusion
This work is the first report on both the mRNA and protein expression of SESN2 in HCC. Differential SESN2 expression was detected in HCC and noncancerous tissue samples, and HCC patients with reduced SESN2 expression levels were prone to suffer positive lymph node metastasis. Moreover, high expression of SESN2 implied advantageous prognosis in HCC patients.