Expression of the Na+/I- symporter (NIS) is markedly decreased or absent in gastric cancer and intestinal metaplastic mucosa of Barrett esophagus

Abstract

Background: The sodium/iodide symporter (NIS) is a plasma membrane glycoprotein that mediates iodide (I-) transport in the thyroid, lactating breast, salivary glands, and stomach. Whereas NIS expression and regulation have been extensively investigated in healthy and neoplastic thyroid and breast tissues, little is known about NIS expression and function along the healthy and diseased gastrointestinal tract.

Methods: Thus, we investigated NIS expression by immunohistochemical analysis in 155 gastrointestinal tissue samples and by immunoblot analysis in 17 gastric tumors from 83 patients.

Results: Regarding the healthy Gl tract, we observed NIS expression exclusively in the basolateral region of the gastric mucin-producing epithelial cells. In gastritis, positive NIS staining was observed in these cells both in the presence and absence of Helicobacter pylori. Significantly, NIS expression was absent in gastric cancer, independently of its histological type. Only focal faint NIS expression was detected in the direct vicinity of gastric tumors, i.e., in the histologically intact mucosa, the expression becoming gradually stronger and linear farther away from the tumor. Barrett mucosa with junctional and fundic-type columnar metaplasia displayed positive NIS staining, whereas Barrett mucosa with intestinal metaplasia was negative. NIS staining was also absent in intestinalized gastric polyps.

Conclusion: That NIS expression is markedly decreased or absent in case of intestinalization or malignant transformation of the gastric mucosa suggests that NIS may prove to be a significant tumor marker in the diagnosis and prognosis of gastric malignancies and also precancerous lesions such as Barrett mucosa, thus extending the medical significance of NIS beyond thyroid disease.

Figure 1

NIS expression in different tissues. A: Radioiodide accumulation in NIS-expressing human tissues (SG: salivary glands, T: thyroid, G: stomach) 2 hours after ^99mTc-pertechnetate administration (5 mCi). B: Immunoblot analyses of human NIS expression in a Graves' thyroid (T), normal salivary glands (SG), and normal gastric mucosa (G). Total protein (50 μg) was electrophoresed into each lane; the nitrocellulose membrane was probed with 3 nM affinity-purified anti-human-NIS Ab as described in Materials and Methods. C-H: Immunohistochemical analyses of NIS expression in human iodide-concentrating tissues. C: Normal thyroid (original magnification: 400 ×), D: Graves' thyroid, strong basolateral NIS staining of the follicular epithelial cells (original magnification: 1,000 ×), E: Salivary gland (original magnification: 400 ×), F: Basolateral NIS staining in the salivary ductal cells (original magnification: 1,000 ×), G: Gastric mucosa (original magnification: 400 ×), H: Basolateral NIS staining of the gastric mucin-secreting cells (original magnification: 1,000 ×).

Figure 2

Immunoblot analysis of gastric NIS expression in human gastric tumors (T) and normal peritumoral tissues (N). A, B, and D: adenocarcinoma, C: MALT lymphoma.

Figure 3

Immunohistochemical analysis of NIS expression in human gastrointestinal tract. a: normal esophageal squamous epithelium (haematoxylin-eosin/HE/staining, original magnification 100×) b: normal esophageal squamous epithelium: negative for NIS expression (original magnification 100×) c: Barrett mucosa (HE staining, original magnification 100×) d: Barrett mucosa, junctional and fundus-type columnar metaplasia: NIS positive staining (original magnification 100×) e: Barrett mucosa with intestinal metaplasia (HE staining, original magnification 100×) f: Barrett mucosa with intestinal metaplasia: negative for NIS expression (original magnification 100×) g: squamous cell esophageal carcinoma (HE staining, original magnification 100×) h: squamous cell esophageal carcinoma: NIS negative staining (original magnification 100×) i: gastric carcinoma – signet ring cell – (HE staining, original magnification 200×) j: gastric carcinoma – signet ring cell – negative for NIS expression (original magnification 200×) k: on the border of the gastric adenocarcinoma, adjacent "normal" extratumoral mucosa: faint, focal NIS expression (original magnification 100×) I: at 1 cm from gastric adenocarcinoma: definite focal NIS staining (original magnification 400×) m: far from the gastric adenocarcinoma: strong, linear NIS expression (original magnification 400×) n: gastric polyp (HE staining, original magnification 100×) o: gastric polyp: NIS positive staining (original magnification 100×) p: gastric polyp (HE staining, original magnification 200×) q: gastric polyp with colon-type metaplasia: NIS negative staining (original magnification 200×) r: small bowel adenocarcinoma (HE staining, original magnification 100×) s: small bowel adenocarcinoma: NIS negative staining (original magnification 100×) t: normal large bowel mucosa: NIS negative staining (original magnification 100×) v: colon polyp (HE staining, original magnification 100×) w: colon polyp: NIS negative expression (original magnification 100×) x: adenocarcinoma of the colon (HE staining, original magnification 100×) y: adenocarcinoma of the colon: negative for NIS expression (original magnification 100×).