Antagonistic Functions of Connexin 43 during the Development of Primary or Secondary Bone Tumors

Abstract

Despite research and clinical advances during recent decades, bone cancers remain a leading cause of death worldwide. There is a low survival rate for patients with primary bone tumors such as osteosarcoma and Ewing’s sarcoma or secondary bone tumors such as bone metastases from prostate carcinoma. Gap junctions are specialized plasma membrane structures consisting of transmembrane channels that directly link the cytoplasm of adjacent cells, thereby enabling the direct exchange of small signaling molecules between cells. Discoveries of human genetic disorders due to genetic mutations in gap junction proteins (connexins) and experimental data using connexin knockout mice have provided significant evidence that gap-junctional intercellular communication (Gj) is crucial for tissue function. Thus, the dysfunction of Gj may be responsible for the development of some diseases. Gj is thus a main mechanism for tumor cells to communicate with other tumor cells and their surrounding microenvironment to survive and proliferate. If it is well accepted that a low level of connexin expression favors cancer cell proliferation and therefore primary tumor development, more evidence is suggesting that a high level of connexin expression stimulates various cellular process such as intravasation, extravasation, or migration of metastatic cells. If so, connexin expression would facilitate secondary tumor dissemination. This paper discusses evidence that suggests that connexin 43 plays an antagonistic role in the development of primary bone tumors as a tumor suppressor and secondary bone tumors as a tumor promoter.

Connexin 43, Bcl-2, Bax, Ki67, and E-cadherin patterns in oral squamous cell carcinoma and its relationship with GJA1 rs12197797 C/G

“…The permeability of Cx43 channels to small molecules and macromolecules makes them very attractive targets for delivering drugs directly to the cytoplasm. Cancer cells that overexpress Cx43 may be more permeable and sensitive to chemotherapeutics ( 29 ).…”

Osteosarcoma-enriched transcripts paradoxically generate osteosarcoma-suppressing extracellular proteins

“…The transcript levels of these candidates were elevated at least two times in OS tissues. We previously showed that extracellular histone H4 and PPIB acted as tumor-suppressing proteins in breast cancer ( Liu et al, 2021a , Sun et al, 2021 ), while the five others were reported to stimulate the progression of OS when present in the intracellular domain ( Chen et al, 2021 ; Wang et al, 2019 ; Zhang et al, 2021 ; Talbot et al, 2020 ; Zhou et al, 2018 ). To examine anti-tumor capabilities, we employed the recombinant proteins (MBS553651, MBS2097677, MBS2009092, MBS2029317, MBS146520, MBS2557159, MBS2031097; MyBioSource), respectively.…”

Osteosarcoma-enriched transcripts paradoxically generate osteosarcoma-suppressing extracellular proteins

“…The transcript levels of these candidates were elevated at least 2 times in OS tissues. We previously showed that extracellular Histone H4 and PPIB acted as tumor-suppressing proteins in breast cancer (Sano et al, 2021, Sun et al, 2021), while the five others were reported to stimulate the progression of OS when present in the intracellular domain (Chen et al, 2021, Wang et al, 2019, Zhang et al, 2021, Talbot et al, 2020, Zhou et al, 2018). To examine anti-tumor capabilities, we employed the recombinant proteins (MBS553651, MBS2097677, MBS2009092, MBS2029317, MBS146520, MBS2557159, MBS2031097; MyBioSource), respectively.…”