在肝硬化的情况下，多种分子改变，比如对凋亡的抵抗等，可能会加速癌变。近年来，机械转导已经成为这些障碍之一的原因之一。在肝硬化患者中，血清钠水平逐渐降低，导致低钠血症。由于肝硬化伴肝癌患者的血清钠水平与癌的数量、大小、阶段和累积存活率呈负相关，我们推测，低渗性引起的机械转导在肝硬化条件下可能有助于肝细胞癌的发生和/或进展。在本研究中，我们通过改变氯化钠浓度来调整培养基水分渗透压，并使用血清剥夺诱导的凋亡模型，研究了低渗压下对HCC细胞系（HepG2）抗凋亡的影响。通过在无血清培养基中培养细胞，可以下调抗凋亡蛋白Bcl-2的水平。相反，低渗压条件通过上调Bcl-2导致抗凋亡能力的增强。接下来，我们研究了哪些通路参与了抗凋亡的过程。低渗压条件增强了AKT信号传导，并且在HepG2细胞中AKT的恒定激活导致Bcl-2的上调。此外，我们揭示了AKT信号增强是由机械感受器TRPV2介导的胞内钙离子内流引起的。我们的研究表明，肝硬化患者低钠血症引起的血清低渗可能促进肝细胞癌的进展。 我们的研究首次揭示了由低渗压引起的机械转导通过TRPV2激活增强钙介导的AKT信号传导，导致抗凋亡的能力增强。这一发现表明，肝硬化引起的低钠血症可能会促进肝细胞癌的发生。

In cirrhosis, several molecular alterations such as resistance to apoptosis could accelerate carcinogenesis. Recently, mechanotransduction has been attracting attention as one of the causes of these disturbances. In patients with cirrhosis, the serum sodium levels progressively decrease in the later stage of cirrhosis, and hyponatremia leads to serum hypo-osmolality. Since serum sodium levels in patients with cirrhosis with liver cancer are inversely related to cancer's number, size, stage, and cumulative survival, we hypothesized that hypo-osmolality-induced mechanotransduction under cirrhotic conditions might contribute to oncogenesis and/or progression of hepatocellular carcinoma (HCC). In this study, we adjusted osmosis of culture medium by changing the sodium chloride concentration and investigated the influence of hypotonic conditions on the apoptosis resistance of an HCC cell line, HepG2, using a serum-deprivation-induced apoptosis model. By culturing the cells in a serum-free medium, the levels of an antiapoptotic protein Bcl-2 were downregulated. In contrast, the hypotonic conditions caused apoptosis resistance by upregulation of Bcl-2. Next, we examined which pathway was involved in the apoptosis resistance. Hypotonic conditions enhanced AKT signaling, and constitutive activation of AKT in HepG2 cells led to upregulation of Bcl-2. Moreover, we revealed that the enhancement of AKT signaling was caused by intracellular calcium influx via a mechanosensor, TRPV2. Our findings suggested that hyponatremia-induced serum hypotonic in patients with cirrhosis promoted the progression of hepatocellular carcinoma.NEW & NOTEWORTHY Our study first revealed that hypo-osmolarity-induced mechanotransduction enhanced calcium-mediated AKT signaling via TRPV2 activation, resulting in contributing to apoptosis resistance. The finding indicates a possible view that liver cirrhosis-induced hyponatremia promotes hepatocellular carcinogenesis.