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ORAI1 channel function is a driver in oral cancer progression and pain

ABSTRACT: Oral cancer causes pain associated with cancer progression. The mechanism(s) underlying the pain is not fully understood. We report here that the function of the Ca2+ channel ORAI1 is an important regulator of oral cancer pain. ORAI1 was highly expressed in tumor samples from oral cancer patients and ORAI1 activation caused sustained Ca2+ influx in human oral cancer cells. RNA-seq analysis showed broad modulation of oral cancer markers such MMPs and pain modulators by ORAI1. Inoculation of oral cancer cells lacking ORAI1 into mouse paws reduced ectopic tumor growth and allodynia, reducing secreted MMP1 levels and the excitation of trigeminal ganglia (TG) neurons. The stimulation of TG neurons with MMP1 evoked an increase in action potentials. These data demonstrate an important role of ORAI1 in oral cancer progression likely by controlling the expression of MMP1 resulting in increased cancer progression and pain

ORGANISM(S): Homo sapiens

PROVIDER: GSE236706 | GEO | 2023/12/27

REPOSITORIES: GEO

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Project description:Systemic lupus erythematous (SLE) is a prototype of autoimmune disease. Lupus nephritis (LN) is one of the most serious complications of SLE. The development of autoreactive B cells and the production of autoantibodies have been critical for the initiation and progression of LN. Store-operated Ca2+ entry (SOCE) is the main Ca2+ influx pathway in lymphocytes and is essential for immune response . SOCE is mediated by Ca2+ release-activated Ca2+ (CRAC) channels which are comprised of stromal interaction molecule (STIM) and calcium release-activated calcium modulators (ORAI) . Mutations in genes encoding the CRAC channel abolish SOCE in cells of the immune system and cause severe combined immunodeficiency . Calcium signaling via ORAI1 has been involved in the pathogenesis of autoimmune diseases by driving Th17 differentiation . STIM1 deficiency significantly reduced Th1/Th17 responses and resulted in complete protection from experimental autoimmune encephalomyelitis . Compared to T cells, the roles of CRAC channel in B cells is far less clear. Ca²⁺/calmodulin (CaM)-dependent protein kinase2 (CaMK2) is a serine/threonine-specific protein kinase that is regulated by the Ca²⁺/CaM complex. CaMK2 has been involved in many signaling pathways and is necessary for Ca²⁺ homeostasis, T cell development and activation. CaMK4, another member of the CaMK family, has been shown to compromises podocyte function and promote renal diseases in LN. In the current study, we found that CRAC channel mediated calcium signaling is enhanced in B cells from patients with LN. CRAC channel inhibition by YM-58483 and knocked down of CRAC channel by ORAI1 or STIM2 siRNA led to suppression of CaMK2 signaling and decreased B cell differentiation. Lupus mice treated with CRAC channel inhibitor showed reduced anti-double stranded DNA antibodies (anti-dsDNA), decreased immune deposition in the glomeruli and improved renal function. CRAC channel mediates the development and progression of LN by promoting the differentiation of B cells into plasma cells.

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ORAI1 channel function is a driver in oral cancer progression and pain

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