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

Abstract

Connexin (Cx)43 is a multifunction protein which forms gap junction channels and hemi‑channels. It also contains abundant binding domains which possess the ability to interact with certain Cx43‑associated proteins and therefore serve a fundamental role in various physiological and pathological functions. However, the understanding of the association between cancer and Cx43 along with Cx43‑gap junctions (GJ) remains unclear. All available data illustrate that Cx43 and its associated GJ serve important functions in cancers. The expression levels of Cx43 demonstrate a downward trend and an increase in the levels of malignancy, particularly in astrocytomas. The GJ intercellular communication activity in glioma cells can be adjusted via Cx43 phosphorylation and through the combination of Cx43 and its associated protein. Available evidence reveals Cx43 as a tumor‑inhibiting factor that suppresses glioma growth and proliferation. However, its mechanism is also regarded as complicated and ambiguous. Furthermore, it is apparent that Cx43‑GJ and the carboxyl tail may contribute to glioma growth and proliferation too. However, this valuable role could be weakened by its effects on migration and invasiveness. The detailed mechanism remains unclear and full of controversies. Cx43 can enhance the motor ability and invasiveness of astrocytic glioma cells. It is also able to influence glioma cells to detach from the tumor core to the peritumoral neocortex. This peritumoral region has recently been regarded as the basic focus of glioma‑associated seizure. Thus, Cx43 may take part in the onset and development of glioma‑associated epileptic discharge. In addition, change and increase of Cx43 expression in GJs has been observed in seizure perilesional tissue, which is associated with brain tumors. Cx43 or GJ/hemi‑channels exert enduring effects in the promotion of glioma‑associated epileptic release through direct mass effects and change of the tumor microenvironment. However, there are still a number of issues concerning this aspect that require further exploration. Cx43, as a potential treatment target against this incurable disease and its common symptom of epilepsy, requires further investigation.

Epilepsy Associates with Decreased HIF-1α/STAT5b Signaling in Glioblastoma

“…STAT5-null mice have indeed undetectable levels of connexin 32 [44], while connexin 43 (Cx43) mediates HIF-1α in astrocytes [45]. High expression of connexin 43 has in turn been linked to both glioma-related [46] and epilepsy due to mesiotemporal sclerosis [47], while this latter presents reduced levels of connexin 32. On the other hand, STAT5 is a negative regulator of xCT Expression and System Xc-Activity [48].…”

Role of Connexins 30, 36, and 43 in Brain Tumors, Neurodegenerative Diseases, and Neuroprotection

“…However, whether Cx36 increases as a compensatory or pathological mechanism is unclear [135]. Hereof, more studies are needed to elucidate the conditions and mechanisms that regulate Cx36 expression in astrocytic tumors because not all glioma cells express Cx36, like the glioma cells F98 [131] Although Cx30, Cx36, and Cx43 are the Cxs with more information available for GBM, they also have a high number of contradictory findings reported [136]. On one side, some studies have related the absence of Cx43 with tumor grade increase, associating this Cx with neoplastic tumor processes.…”

Lcn2-derived Circular RNA (hsa_circ_0088732) Inhibits Cell Apoptosis and Promotes EMT in Glioma via the miR-661/RAB3D Axis

“…The development of glioma is a complex biological process that involves multiple mechanisms and factors (10,11). Numerous tumor suppressor genes, oncogenes, and growth factors have been confirmed to be involved in glioma progression (12)(13)(14).…”