Date Published: March 28, 2017
Publisher: Public Library of Science
Author(s): Youzhu Lu, Jingjing Jing, Liping Sun, Yuehua Gong, Moye Chen, Zeyang Wang, Mingjun Sun, Yuan Yuan, Masaru Katoh.
Claudins play an important role in regulating the permeability of epithelial and endothelial cells and in the maintenance of cell polarity. We aimed to investigate expression of claudin-11, -23 in different gastric tissues and its relationship with clinicopathologic parameters and prognosis of gastric cancer. We compared their expression levels in the paired cancerous tissues versus those in the adjacent noncancerous tissues by real-time PCR, western blotting and immunohistochemistry. The results showed that the expression of claudin-11, -23 was greatly increased in paracancerous gastric tissue compared with cancerous tissue. We also compared their expression levels of tissues from gastric cancer, superficial gastritis, and atrophic gastritis by immunohistochemistry. The results indicated that the expression of claudin-11 and 23 was significantly higher in superficial gastritis than that in atrophic gastritis and gastric cancer. The expression of claudin-23 was significantly lower in atrophic gastritis than that in gastric cancer, but no obviously difference was observed for claudin-11. As for analysis of clinicopathologic parameters of gastric cancer, logistic multiple regression indicated that claudin-11 was significantly associated with sex, smoking, alcohol, H. pylori infection and Borrmann classification while claudin-23 was significantly associated with vessel cancer embolus. Cox multivariate survival analysis indicated that gastric cancer patients with negative claudin-23 expression had significantly longer overall survival. In conclusion, the expression of claudin-11, -23 was remarkably downregulated in gastric cancer. Abnormal expression of these proteins was significantly correlated with some clinicopathologic parameters. In particular, claudin-23 positive expression was associated with poor prognostic outcomes of gastric cancer patients and may therefore serve as an independent prognosticator of patient survival.
The gastric mucosal barrier is an important defensive mechanism that can protect gastric mucosa and prevent the occurrence of gastric diseases. The integrity of its structure and function not only prohibits diffusion of H+ from the gastric cavity to gastric mucosa and of Na+ from mucosa to the gastric cavity, but also defends against the invasion of harmful factors. The gastric mucosal barrier is mainly composed of epithelial cells and intracellular junctions. The tight junction, a multicomplex of membrane proteins, is the most essential component of the intracellular junction structure. Tight junction transmembrane proteins known as claudins, a family of 27 proteins, play a critical role in the maintenance of cell polarity and barrier function and in the permeability of epithelial cells [1–3]. Abnormal expression and distribution of claudin proteins may disrupt the structure and function of tight junctions, leading to damage of the gastric mucosal barrier and thereby allowing abnormal lateral diffusion of intracellular molecules and the invasion of bacteria and virulence factors from gastric mucosa into the organic body, which may result in the occurrence of many kinds of gastric diseases and even gastric cancer . For example, claudin-1, which is highly expressed in the intestinal type of gastric cancer, is correlated with tumor invasion and migration and poor prognosis and overexpression of claudin-1 may promote the proliferation and migration of gastric cancer cells [5–7]. Downregulation of claudin-18 has been shown to be related to proliferation and migration of gastric cancer cells . Moreover, some studies suggest that abnormal changes in claudin proteins may lead to the invasion, metastasis, and recurrence of gastric tumor, irrespective of early or late stage [9–11]. Therefore, abnormal expression of claudins may be closely related to the occurrence, progression, and prognosis of gastric cancer.
Claudin proteins are critical for tight junction function, and their up/downregulation can disrupt the structure and function of tight junctions, leading to the loss of intracellular adhesion and loss of homeostasis . In addition, abnormal expression of claudin proteins can affect cell proliferation, differentiation, apoptosis, and invasion through many signaling pathways that play important roles in the progression of cancer . In this study, we focused on two major members of the claudin family, claudin-11, -23, and examined their expression in gastric cancer, atrophic gastritis, and superficial gastritis. Moreover, we investigated the relationships between expression of claudin-11, -23 and clinicopathologic parameters and survival in gastric cancer.