Introduction Hepatocarcinoma is a common and aggressive form

Introduction Hepatocarcinoma is a common and aggressive form of cancer (Trad et al., 2017). Due to a high rate of postoperative recurrence and metastasis, the prognosis for HCC remains dismal (Wang et al., 2017a, 2017b). Subclinical metastasis is the major cause responsible for tumor recurrence and patient mortality (Alshahrani et al., 2018). Therefore, exploration of biological biomarkers related to metastasis of HCC could be both meaningful and translational in light of no reliable biomarker for metastasis of HCC. Chloride channel 3, also known as CLCN3 or CIC-3, which encodes a member of the voltage-gated chloride channel (ClC) family (Duan et al., 1997). The encoded protein CIC-3 was found to be present in all cell types and localized in plasma membranes and in intracellular vesicles, mediating the exchange of chloride ions against protons (Habela et al., 2009). Physiologically, CIC-3 functioned as antiporter contributing to the acidification of the endosome and synaptic vesicle lumen, thereby may affect vesicle trafficking and exocytosis. With the understanding of CIC-3, clinically, several diseases have been discovered to be associated with aberrant expression of CIC-3, included GSK-923295 receptor (Gentzsch et al., 2003), neuronal ceroid lipofuscinosis (Yoshikawa et al., 2002), allergic rhinitis(Li et al., 2008), myocardial ischemia (Yu et al., 2016)and carcinomas of different types. Several lines of evidence suggested that aberrant expression of CIC-3 was associated with metastasis of cancers (Wang et al., 2017a, 2017b, Tamborini et al., 2016; Xu et al., 2015; Sontheimer, 2008). Despite this, little report actually has been available regarding the clinicopathological significance of CIC-3 expression status in the setting of hepatocarcioma, especially on clinical tissue level. Suggested by these earlier studies related to CIC-3, we reasoned that CIC-3 might be linked with metastasis in hepatocarcinoma as well. To test the hypothesis, we performed immunohistochemistry, statistically analyzing the pathological significance of CIC-3 expression in hepatocarcinoma tissues. It turned out to be that markedly up-regulated CIC-3 was only linked with tumor size and unfavorable overall prognosis in hepatocarcioma, independent of metastasis, indicating that CIC-3 expression was unassociated with metastasis but could predict both the tumor size and poor overall prognosis in hepatocarcinoma.
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Results
Discussion In effect, CIC-3 was identified to be present in all cell types and be subcellularly localized in plasma membranes and in intracellular vesicles (Hagos et al., 1999). In terms of the physiological roles mediated by CIC-3, it has been found to play its part in both acidification (Li et al., 2002) and transmitter loading of GABAergic synaptic vesicles(Ahnert-Hilger and Jahn, 2011). Moreover, lines of evidence revealed that CIC-3 was also required for Cl-current activity (Robinson et al., 2004; Lemonnier et al., 2004) and fibroblast to myofibroblast differentiation (Yin et al., 2008). By contrast, it was comparatively less well understood in the context of cancer than its implication in physiological setting. In actuality, the first evidence regarding CIC-3 in cancer came from the carcinoma of prostate (Lemonnier et al., 2004). Subsequently, it was extended to other different types of carcinomas, including nasopharyngus (Wang et al., 2004; Mao et al., 2008), neuroendocrine (Weylandt et al., 2007), brain(Sontheimer, 2008; Cuddapah and Sontheimer, 2010), breast (Macpherson et al., 2014) and liver (Li et al., 2002; Mao et al., 2011, 2013). Despite there were a few reports have emerged concerning CIC-3 in hepatocellular carcinoma; regrettably, all of which were principally mechanistic exploration that came from in vitro cell culture system involving hepatoma cell lines (Li et al., 2002; Mao et al., 2011, 2013) and short of clinicopathological meaning on tissue level. Little was known, therefore, in relation to the clinicopathological meaning of CIC-3 expression in hepatocarcinoma. Considering this, we were determined to investigate and analyze the clinicopathological significance of CIC-3 expression in hepatocarcinoma tissues, where there has been seldom reported till now.