Biology subjects

Sayedyahossein, S.

Publications and source records attributed to Sayedyahossein, S..

3 recordsLinked to original sources

bioRxiv2024

Pannexin 1 and Pannexin 3 differentially regulate the tumorigenic properties of cutaneous squamous cell carcinoma

Pannexin (PANX) channels are present in skin and facilitate the movement of signalling molecules during cellular communication. PANX1 and PANX3 function in skin homeostasis and keratinocyte differentiation but were previously reduced in a small cohort of human cutaneous squamous cell carcinoma (cSCC) tumours compared to normal epidermis. In our study, we used SCC-13 cells, limited publicly available RNA-seq data and a larger cohort of cSCC patient-matched samples to analyze PANX1 and PANX3 expression and determine the association between their dysregulation and the malignant properties of cSCC. In a bioinformatics analysis, PANX1 transcripts were increased in cSCC and head and neck SCC tumours compared to normal tissues, but PANX3 mRNA showed no differences. However, in our own cohort, PANX3 transcripts were decreased in cSCC compared to patient-matched aged skin, whereas PANX1 was upregulated in cSCC. PANX1 localized to all regions within the cSCC tumour microenvironment and increased levels were associated with larger tumour dimensions. To investigate PANX1 function in SCC-13 cells, we deleted PANX1 via CRISPR/Cas9 and treated with PANX1 inhibitors which markedly reduced cell growth and migration. To assess PANX3 function in cutaneous carcinogenesis, we employed the DMBA/TPA model using our global Panx3 knockout (KO) mice, where 60% of wildtype and 100% of KO mice formed pre-cancerous papillomas. Average papilloma volumes at endpoint were significantly increased in KO mice and showed moderate evidence of increases in KO mice over time. Collectively, these findings suggest PANX1 and PANX3 dysregulation may have potential tumour promoting and suppressive effects for keratinocyte transformation, respectively. Key points summaryO_LIPannexin 1 and pannexin 3 are channel-forming proteins which are critical in the normal maintenance and function of keratinocytes in the skin but may become altered in cutaneous squamous cell carcinoma (cSCC) tumours. C_LIO_LIIn this study, we used a combination of culture models, mouse models and patient-derived tissues. We found pannexin 1 levels are increased in cSCC tumours and present in all tumour regions, functioning to promote cSCC cell growth and migration. C_LIO_LIConversely, pannexin 3 levels are decreased in cSCC tumours and this protein reduces the incidence and growth of pre-cancerous lesions. C_LIO_LITaken together, our data indicates that in cSCC these pannexin family members seem to have opposite effects, where pannexin 1 is pro-tumorigenic and pannexin 3 is anti-tumorigenic. C_LIO_LIThese results help us to better understand the mechanisms of malignant transformation of keratinocytes and offer a new potential therapeutic target for the treatment of advanced cSCC. C_LI

cancer biology↗

bioRxiv2022

Pannexin 3 channels regulate architecture, adhesion, barrier function and inflammation in the skin

The channel-forming glycoprotein Pannexin 3 (PANX3) functions in cutaneous wound healing and keratinocyte differentiation, but its role in skin homeostasis through aging is not yet understood. We found that PANX3 is absent in newborn skin but becomes upregulated with age. We characterized the skin of global Panx3 knockout mice (KO) and found that KO dorsal skin showed sex-differences at different ages, but generally had reduced dermal and hypodermal areas compared to aged-matched controls. Transcriptomic analysis of KO epidermis revealed reduced E-cadherin stabilization and Wnt signaling compared to WT, consistent with the inability of primary KO keratinocytes to adhere in culture, and diminished epidermal barrier function in KO mice. We also observed increased inflammatory signaling in KO epidermis and higher incidence of dermatitis in aged KO mice compared to wildtype controls. These findings suggest that during skin aging, PANX3 is critical in the maintenance of dorsal skin architecture, keratinocyte cell-cell and cell-matrix adhesion and inflammatory skin responses.

cell biology↗

bioRxiv2021

Pannexin 3 deletion reduces fat accumulation and inflammation in a sex-specific manner

BackgroundPannexin 3 (PANX3), is a channel-forming glycoprotein that enables nutrient-induced inflammation in vitro, and genetic linkage data suggests it regulates body mass index. Here, we characterized inflammatory and metabolic parameters in global Panx3 knockout (KO) mice in the context of forced treadmill running (FEX) and high fat diet (HFD). MethodsC57BL/6N (WT) and KO mice were randomized to either a FEX running protocol or no running (SED) from 24 until 30 weeks of age. Body weight was measured biweekly, and body composition was measured at 24 and 30 weeks of age. Male WT and KO mice were fed a HFD from 12 - 28 weeks of age. Metabolic organs were analyzed for a panel of inflammatory markers and PANX3 expression. ResultsIn females there were no significant differences in body composition between genotypes, which could be due to the lack of PANX3 expression in female white adipose tissue, while male KOs fed a chow diet had lower body weight, and lower fat mass at 24 and 30 weeks of age, which was reduced to the same extent as 6 weeks of FEX in WT mice. Additionally, male KO mice exhibited significantly lower expression of multiple pro-inflammatory genes in white adipose tissue compared to WT mice. While on a HFD body weight differences were insignificant, in KO mice, multiple inflammatory genes were significantly differently expressed in quadriceps muscle and white adipose tissue resulting in a more anti-inflammatory phenotype compared to WT mice. The lower fat mass in male KO mice may be due to significantly fewer adipocytes in their subcutaneous fat compared to WT mice. Mechanistically, adipose stromal cells (ASCs) cultured from KO mice grow significantly slower than WT ASCs. ConclusionPANX3 is expressed in male adult mouse adipose tissue and may regulate adipocyte numbers, influencing fat accumulation and inflammation.

physiology↗