Expression of a gap junction protein, connexin43, in a large panel of human gliomas: new insights

Abstract

Precise diagnosis of low and high grades of brain tumors permits determining therapeutical strategies. So far, diagnosis and prognosis of gliomas were based on histological and genetic criteria which need being completed by a panel of molecular markers. Highly distributed in brain, gap junction proteins, connexins, could be considered as markers of glioma progression as previous studies indicated that expression of a connexin type, connexin43 (Cx43), is inversely correlated to tumor grading. However, this assumption was weakened by the low number of glioma samples used. Taking advantage of tissue microarray technique, we pursued this analysis by studying in situ expression of Cx43 on 85 samples (37 grade IV, 18 grade III, 24 grade II, and 6 grades II to III). Our analysis confirmed the global diminution of Cx43 expression in glioblastomas that was observed in previous studies. However, this analysis brought new insights such as the following ones. First, the high number of samples permitted to show that more than 60% of glioblastomas still express Cx43. Second, no gradual decrease in Cx43 expression was observed between grades II and III, but Cx43 appeared to be a marker distinguishing oligodendrocytic and astrocytic grade III tumors. Third, independently from tumor grade, a Cx43 nuclear staining was detected in areas where leukocytes are present. In conclusion, our study emphasizes the importance of in situ immunohistochemical approaches by giving more precise insights in the subcellular localization of Cx43. It also emphasizes the necessity to carry out such analysis on a wide range of samples to circumvent the high glioma heterogeneity.

Novel approach to temozolomide resistance in malignant glioma: connexin43-directed therapeutics

“…While these data are consistent with the hypothesis that Cx43 is a tumor suppressor, ongoing research has revealed novel functions of Cx43 in GBM disease progression and therapeutic responses. In three studies using a much larger cohort of GBM patients (16, 37, and 74 specimens, respectively), percentages of patients expressing Cx43 were 62.2%, 62.5%, and 77%, respectively [13,21 • ,22]. A report by Cottin and colleagues further determined that more than 10% of GBM tumors (9 out of 74) displayed strong Cx43 immunostaining [22].…”

“…Furthermore, characterization of 10 GSCs lines derived from established cell lines, xenografts, and freshly dissected patient tumor tissues indicated variation in self-renewal capabilities, gene expression profiles, and chemotherapeutic susceptibility [16 •• ]. Recent reports also emphasize the importance of Cx43 subcellular localization and how these findings may translate to recently reported in vitro findings [21 • ]. Given that expression and localization of Cx43 in the nucleus and cytoplasm has been shown to reduce the growth of human GBM cells without a corresponding change in GJIC [19], further investigation into the molecular interactions and signaling pathways that may be impacted by Cx43 subcellular localization and what roles these may play in glioma progression and chemotherapeutic resistance is warranted.…”

Complex role of connexin 43 in astrocytic tumors and possible promotion of glioma-associated epileptic discharge

“…It is also decreased in the majority of GBM, where the expression of Cx43 protein is insignificant (12,26,27). However, Crespin et al (28) did not share this point of view. First, in spite of the modest inverse association between tumor grade and Cx43 expression, over half of glioblastomas still express Cx43.…”

The effects of cucurbitacin E on GADD45β‐trigger G2/M arrest and JNK‐independent pathway in brain cancer cells

“…[3][4][5] Cucurbitacins, a class of tetracyclic triterpenoids with medicinal properties in Cucurbitaceae, are extracted from the climbing stems of Cucumis melo L. 6 Cucurbitacins have been widely used in inhibition of cancer cell progression as medicinal herbs throughout Asia. 1 However, the chemotherapy for brain cancer remains obscure.…”