Sodium-coupled Monocarboxylate Transporters in Normal Tissues and in Cancer

SLC5A8 and SLC5A12 are sodium-coupled monocarboxylate transporters (SMCTs), the former being a high-affinity type and the latter a low-affinity type. Both transport a variety of monocarboxylates in a Na+-coupled manner. They are expressed in the gastrointestinal tract, kidney, thyroid, brain, and retina. SLC5A8 is localized to the apical membrane of epithelial cells lining the intestinal tract and proximal tubule. In the brain and retina, its expression is restricted to neurons and the retinal pigment epithelium. The physiologic functions of SLC5A8 include absorption of short-chain fatty acids in the colon and small intestine, reabsorption of lactate and pyruvate in the kidney, and cellular uptake of lactate and ketone bodies in neurons. It also transports the B-complex vitamin nicotinate. SLC5A12 is also localized to the apical membrane of epithelial cells lining the intestinal tract and proximal tubule. In the brain and retina, its expression is restricted to astrocytes and Müller cells. SLC5A8 also functions as a tumor suppressor; its expression is silenced in tumors of colon, thyroid, stomach, kidney, and brain. The tumor-suppressive function is related to its ability to mediate concentrative uptake of butyrate, propionate, and pyruvate, all of which are inhibitors of histone deacetylases. SLC5A8 can also transport a variety of pharmacologically relevant monocarboxylates, including salicylates, benzoate, and γ-hydroxybutyrate. Non-steroidal anti-inflammatory drugs such as ibuprofen, ketoprofen, and fenoprofen, also interact with SLC5A8. These drugs are not transportable substrates for SLC5A8, but instead function as blockers of the transporter. Relatively less is known on the role of SLC5A12 in drug transport

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

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

Zinc Sensing Receptor Signaling, Mediated by GPR39, Reduces Butyrate-Induced Cell Death in HT29 Colonocytes via Upregulation of Clusterin

Zinc enhances epithelial proliferation, protects the digestive epithelial layer and has profound antiulcerative and antidiarrheal roles in the colon. Despite the clinical significance of this ion, the mechanisms linking zinc to these cellular processes are poorly understood. We have previously identified an extracellular Zn2+ sensing G-protein coupled receptor (ZnR) that activates Ca2+ signaling in colonocytes, but its molecular identity as well as its effects on colonocytes' survival remained elusive. Here, we show that Zn2+, by activation of the ZnR, protects HT29 colonocytes from butyrate induced cell death. Silencing of the G-protein coupled receptor GPR39 expression abolished ZnR-dependent Ca2+ release and Zn2+-dependent survival of butyrate-treated colonocytes. Importantly, GPR39 also mediated ZnR-dependent upregulation of Na+/H+ exchange activity as this activity was found in native colon tissue but not in tissue obtained from GPR39 knock-out mice. Although ZnR-dependent upregulation of Na+/H+ exchange reduced the cellular acid load induced by butyrate, it did not rescue HT29 cells from butyrate induced cell death. ZnR/GPR39 activation however, increased the expression of the anti-apoptotic protein clusterin in butyrate-treated cells. Furthermore, silencing of clusterin abolished the Zn2+-dependent survival of HT29 cells. Altogether, our results demonstrate that extracellular Zn2+, acting through ZnR, regulates intracellular pH and clusterin expression thereby enhancing survival of HT29 colonocytes. Moreover, we identify GPR39 as the molecular moiety of ZnR in HT29 and native colonocytes

Mechanism of anion selectivity and stoichiometry of the Na+/I- symporter (NIS)

I(-) uptake in the thyroid, the first step in thyroid hormone biosynthesis, is mediated by the Na(+)/I(-) symporter (NIS) with an electrogenic 2Na(+):1I(-) stoichiometry. We have obtained mechanistic information on NIS by characterizing the congenital I(-) transport defect-causing NIS mutant G93R. This mutant is targeted to the plasma membrane but is inactive. Substitutions at position 93 show that the longer the side chain of the neutral residue at this position, the higher the K(m) for the anion substrates. Unlike WT NIS, which mediates symport of Na(+) and the environmental pollutant perchlorate electroneutrally, G93T/N/Q/E/D NIS, strikingly, do it electrogenically with a 21 stoichiometry. Furthermore, G93E/Q NIS discriminate between anion substrates, a discovery with potential clinical relevance. A 3D homology model of NIS based on the structure of the bacterial Na(+)/galactose transporter identifies G93 as a critical player in the mechanism of the transporter: the changes from an outwardly to an inwardly open conformation during the transport cycle use G93 as a pivo

Na(+)/monocarboxylate transport (SMCT) protein expression correlates with survival in colon cancer: Molecular characterization of SMCT

We report an extensive characterization of the Na(+)/monocarboxylate transporter (SMCT), a plasma membrane protein that mediates active transport of monocarboxylates such as propionate and nicotinate, and we show that SMCT may play a role in colorectal cancer diagnosis. SMCT, the product of the SLC5A8 gene, is 70% similar to the Na(+)/I(−) symporter, the protein that mediates active I(−) uptake in the basolateral surface of thyrocytes and other cells. SMCT was reported in the apical surface of thyrocytes and formerly proposed also to transport I(−) and was called the apical I(−) transporter. However, it is now clear that SMCT does not transport I(−). Here we demonstrate a high-affinity Na(+)-dependent monocarboxylate transport system in thyroid cells, which is likely to be SMCT. We show that, whereas thyroidal Na(+)/I(−) symporter expression is thyroid-stimulating hormone (TSH)-dependent and basolateral, SMCT expression is TSH-independent and apical not only in the thyroid but also in kidney and colon epithelial cells and in polarized Madin–Darby canine kidney cells. We determine the kinetic parameters of SMCT activity and show its inhibition by ibuprofen (K(i) = 73 ± 9 μM) in Xenopus laevis oocytes. SMCT was proposed to be a tumor suppressor in colon cancer [Li, H., et al. (2003) Proc. Natl. Acad. Sci. USA 100, 8412–8417]. Significantly, we show that higher expression of SMCT in colon samples from 113 colorectal cancer patients correlates with longer disease-free survival, suggesting that SMCT expression may be a favorable indicator of colorectal cancer prognosis

Meaningful words in rectal MRI synoptic reports: How “polypoid” may be prognostic

PurposeThis study explored the clinicopathologic outcomes of rectal tumor morphological descriptors used in a synoptic rectal MRI reporting template and determined that prognostic differences were observed.MethodsThis retrospective study was conducted at a comprehensive cancer center. Fifty patients with rectal tumors for whom the synoptic descriptor "polypoid" was chosen by three experienced radiologists were compared with ninety comparator patients with "partially circumferential" and "circumferential" rectal tumors. Two radiologists re-evaluated all cases. The outcome measures were agreement among two re-interpreting radiologists, clinical T staging with MRI (mrT) and descriptive nodal features, and degrees of wall attachment of tumors (on MRI) compared with pathological (p) T and N stage when available.ResultsRe-evaluation by two radiologists showed moderate to excellent agreement in tumor morphology, presence of a pedicle, and degree of wall attachment (k = 0.41-0.76) and excellent agreement on lymph node presence and size (ICC = 0.83-0.91). Statistically significant lower mrT stage was noted for polypoid morphology, wherein 98% were mrT1/2, while only 7% and 2% of partially circumferential and circumferential tumors respectively were mrT1/2. Pathologic T and N stages among the three morphologies also differed significantly, with only 14% of polypoid cases higher than stage pT2 compared to 48% of partially circumferential cases and 60% of circumferential cases.ConclusionUsing a "polypoid" morphology in rectal cancer MRI synoptic reports revealed a seemingly distinct phenotype with lower clinical and pathologic T and N stages when compared with alternative available descriptors.Precis"Polypoid" morphology in rectal cancer confers a lower clinical and pathologic T and N stage and may be useful in determining whether to proceed with surgery versus neoadjuvant treatment

Radiomics-based prediction of microsatellite instability in colorectal cancer at initial computed tomography evaluation

PURPOSE:To predict microsatellite instability (MSI) status of colon cancer on preoperative CT imaging using radiomic analysis. METHODS:This retrospective study involved radiomic analysis of preoperative CT imaging of patients who underwent resection of stage II-III colon cancer from 2004 to 2012. A radiologist blinded to MSI status manually segmented the tumor region on CT images. 254 Intensity-based radiomic features were extracted from the tumor region. Three prediction models were developed with (1) only clinical features, (2) only radiomic features, and (3) "combined" clinical and radiomic features. Patients were randomly separated into training (n = 139) and test (n = 59) sets. The model was constructed from training data only; the test set was reserved for validation only. Model performance was evaluated using AUC, sensitivity, specificity, PPV, and NPV. RESULTS:Of the total 198 patients, 134 (68%) patients had microsatellite stable tumors and 64 (32%) patients had MSI tumors. The combined model performed slightly better than the other models, predicting MSI with an AUC of 0.80 for the training set and 0.79 for the test set (specificity = 96.8% and 92.5%, respectively), whereas the model with only clinical features achieved an AUC of 0.74 and the model with only radiomic features achieved an AUC of 0.76. The model with clinical features alone had the lowest specificity (70%) compared with the model with radiomic features alone (95%) and the combined model (92.5%). CONCLUSIONS:Preoperative prediction of MSI status via radiomic analysis of preoperative CT adds specificity to clinical assessment and could contribute to personalized treatment selection