Abstract
MAP17 is a membrane-associated protein that is overexpressed in human tumors. Because the expression of MAP17 increases reactive oxygen species (ROS) generation through SGLT1 in cancer cells, in the present work, we investigated whether MAP17 and/or SGLT1 might be markers for the activity of treatments involving oxidative stress, such as cisplatin or radiotherapy. First, we confirmed transcriptional alterations in genes involved in the oxidative stress induced by MAP17 expression in HeLa cervical tumor cells and found that Hela cells expressing MAP17 were more sensitive to therapies that induce ROS than were parental cells. Furthermore, MAP17 increased glucose uptake through SGLT receptors. We then analyzed MAP17 and SGLT1 expression levels in cervical tumors treated with cisplatin plus radiotherapy and correlated the expression levels with patient survival. MAP17 and SGLT1 were expressed in approximately 70% and 50% of cervical tumors of different types, respectively, but they were not expressed in adenoma tumors. Furthermore, there was a significant correlation between MAP17 and SGLT1 expression levels. High levels of either MAP17 or SGLT1 correlated with improved patient survival after treatment. However, the patients with high levels of both MAP17 and SGLT1 survived through the end of this study. Therefore, the combination of high MAP17 and SGLT1 levels is a marker for good prognosis in patients with cervical tumors after cisplatin plus radiotherapy treatment. These results also suggest that the use of MAP17 and SGLT1 markers may identify patients who are likely to exhibit a better response to treatments that boost oxidative stress in other cancer types.
Highlights
MAP17 is a small (17 kDa), non-glycosylated, membraneassociated protein located in the plasma membrane and Golgi apparatus [1]
We explored whether increases in MAP17 and its effector SGLT1 serve as prognostic markers for improved survival in patients with cervical tumors currently treated with cisplatin and radiation therapy
Some genes, such as PTGS1 (39-fold increase) or SIRT2 (10-fold increase), were clearly upregulated, while BNIP3 or MSRA (18-fold decrease) were downregulated (Table 1). These data clearly indicate that MAP17 overexpression in Hela cells altered the RNA levels of genes regulating oxidative stress, and this altered the levels of reactive oxygen species (ROS) produced in Hela cells (Figure S1)
Summary
MAP17 is a small (17 kDa), non-glycosylated, membraneassociated protein located in the plasma membrane and Golgi apparatus [1]. MAP17 acts as an atypical anchoring site for PDZK1 and interacts with the NaPi-IIa/ PDZK1 protein complex in renal proximal tubular cells [3]. The physiological role of MAP17 in proximal tubules is not well known; MAP17 stimulates SGLT transporters, increasing specific Na-dependent transport of mannose and glucose in Xenopus oocytes [1] and human tumor cells [4]. MAP17 is overexpressed, primarily through mRNA amplification, in a variety of human carcinomas [5,6,7]. Immunohistochemical analysis of MAP17 during cancer progression shows that overexpression strongly correlates with tumoral progression in prostate, breast and ovarian carcinomas [6,7]. Generalized MAP17 overexpression in human carcinomas indicates that
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