Huina Wang

Xeroderma Pigmentosum Group A Promotes Autophagy to Facilitate Cisplatin Resistance in Melanoma Cells through the Activation of PARP1

Xeroderma pigmentosum group A (XPA), a key protein in the nucleotide excision repair pathway, has been shown to promote the resistance of tumor cells to chemotherapeutic drugs by facilitating the DNA repair process. However, the role of XPA in the resistance of melanoma to platinum-based drugs like cisplatin is largely unknown. In this study, we initially found that XPA was expressed at higher levels in cisplatin-resistant melanoma cells than in cisplatin-sensitive ones. Furthermore, the knockdown of XPA not only increased cellular apoptosis but also inhibited cisplatin-induced autophagy, which rendered the melanoma cells more sensitive to cisplatin. Moreover, we discovered that the increased XPA in resistant melanoma cells promoted poly(adenosine diphosphate-ribose) polymerase 1 (PARP1) activation and that the inhibition of PARP1 could attenuate the cisplatin-induced autophagy. Finally, we proved that the inhibition of PARP1 and the autophagy process made resistant melanoma cells more susceptible to cisplatin treatment. Our study shows that XPA can promote cell-protective autophagy in a DNA repair-independent manner by enhancing the activation of PARP1 in melanoma cells resistant to cisplatin and that the XPA-PARP1-mediated autophagy process can be targeted to overcome cisplatin resistance in melanoma chemotherapy.

Proinflammatory effect of high-mobility group protein B1 on keratinocytes: an autocrine mechanism underlying psoriasis development.

Psoriasis is an autoimmune skin disease, in which keratinocytes play a crucial pathogenic role. High‐mobility group protein B1 (HMGB1) is an inflammatory factor that can be released from keratinocyte nuclei in psoriatic lesions. We aimed to investigate the proinflammatory effect of HMGB1 on keratinocytes and the contribution of HMGB1 to psoriasis development. Normal human keratinocytes were treated with recombinant human HMGB1, and the production of inflammatory factors and the intermediary signalling pathways were examined. Furthermore, the imiquimod‐induced psoriasis‐like mouse model was used to investigate the role of HMGB1 in psoriasis development in vivo. A total of 11 inflammatory factors were shown to be upregulated by HMGB1 in keratinocytes, among which interleukin (IL)‐18 showed the greatest change. We then found that activation of the nuclear factor‐κB signalling pathway and inflammasomes accounted for HMGB1‐induced IL‐18 expression and secretion. Moreover, HMGB1 and downstream IL‐18 contributed to the development of psoriasiform dermatitis in the imiquimod‐treated mice. In addition, T‐helper 17 immune response in the psoriasis‐like mouse model could be inhibited by both HMGB1 and IL‐18 blockade. Our findings indicate that HMGB1 secreted from keratinocytes can facilitate the production and secretion of inflammatory factors such as IL‐18 in keratinocytes in an autocrine way, thus promoting the development of psoriasis. Blocking the proinflammatory function of the HMGB1–IL‐18 axis may be useful for psoriasis treatment in the future. Copyright

Proinflammatory effect of HMGB1 on keratinocytes: an autocrine mechanism underlying psoriasis development

Psoriasis is an autoimmune skin disease, in which keratinocytes play a crucial pathogenic role. High‐mobility group protein B1 (HMGB1) is an inflammatory factor that can be released from keratinocyte nuclei in psoriatic lesions. We aimed to investigate the proinflammatory effect of HMGB1 on keratinocytes and the contribution of HMGB1 to psoriasis development. Normal human keratinocytes were treated with recombinant human HMGB1, and the production of inflammatory factors and the intermediary signalling pathways were examined. Furthermore, the imiquimod‐induced psoriasis‐like mouse model was used to investigate the role of HMGB1 in psoriasis development in vivo. A total of 11 inflammatory factors were shown to be upregulated by HMGB1 in keratinocytes, among which interleukin (IL)‐18 showed the greatest change. We then found that activation of the nuclear factor‐κB signalling pathway and inflammasomes accounted for HMGB1‐induced IL‐18 expression and secretion. Moreover, HMGB1 and downstream IL‐18 contributed to the development of psoriasiform dermatitis in the imiquimod‐treated mice. In addition, T‐helper 17 immune response in the psoriasis‐like mouse model could be inhibited by both HMGB1 and IL‐18 blockade. Our findings indicate that HMGB1 secreted from keratinocytes can facilitate the production and secretion of inflammatory factors such as IL‐18 in keratinocytes in an autocrine way, thus promoting the development of psoriasis. Blocking the proinflammatory function of the HMGB1–IL‐18 axis may be useful for psoriasis treatment in the future. Copyright

Aberrant SIRT6 expression contributes to melanoma growth: Role of the autophagy paradox and IGF-AKT signaling

ABSTRACT Melanoma is among the most life-threatening cancers. The pathogenesis of melanoma has not been fully elucidated. Recently, dysregulated macroautophagy/autophagy has been found to play a critical but inconsistent role in modulating melanoma growth at different stages, with the regulatory mechanism unclear. The histone deacetylase SIRT6 (sirtuin 6) is a known autophagy regulator, and its involvement in cancer development has been reported. Therefore, we sought to determine the role of SIRT6 in melanoma growth and detect its possible link with autophagy in the current study. We initially observed that the expression of SIRT6 decreased in primary melanoma but increased in metastatic melanoma compared with melanocytic nevus. Notably, the expression of SIRT6 was significantly correlated with the expression of autophagy biomarkers including MAP1LC3/LC3 and SQSTM1/p62. Furthermore, SIRT6 suppressed the growth of primary melanoma but promoted metastatic melanoma development in an autophagy-dependent way in vitro. Moreover, SIRT6 exerted its regulation on melanoma growth via the IGF-AKT signaling pathway, and the intervention of AKT could partly reverse the effects of SIRT6 on melanoma growth by regulating autophagy. At last, we determined the effects of SIRT6 on melanoma development in vivo. Taken together, our findings demonstrate that the bimodal expression of SIRT6 at different melanoma stages plays a critical role in regulating melanoma growth through an autophagy-dependent manner, which indicates the potential of SIRT6 to be a biomarker and a therapeutic target in melanoma.

MicroRNA-340 inhibits squamous cell carcinoma cell proliferation, migration and invasion by downregulating RhoA

BACKGROUND MicroRNAs are reported to play an important role in tumor growth and metastasis, including squamous cell carcinoma (SCC). Accumulative evidence has revealed that dysregulated miR-340 expression contributed to the carcinogenesis and development of various cancers. OBJECTIVE The aim of the current study was to investigate the role and the underlying mechanism of miR-340 in SCC cell proliferation, migration and invasion. METHODS Quantitative real-time PCR was performed to examine the expression of miR-340 in SCC tissues and cell lines. The function of miR-340 in SCC was investigated through Cell Counting Kit-8, wound healing, transwell migration and invasion assays. Bioinformatics analysis, luciferase reporter assay, western blotting and immunohistochemical analysis were conducted to predict and confirm the target gene of miR-340. RESULTS In the present study, we first found that miR-340 was significantly decreased in both SCC tissues and cell lines. Moreover, ectopic expression of miR-340 remarkably attenuated SCC cell proliferation, migration and invasion, whereas inhibition of endogenous miR-340 promoted SCC cell proliferation, migration and invasion in vitro. Our subsequent bioinformatics analysis and luciferase reporter assay showed that RhoA was a novel direct target of miR-340 in SCC cells, and the knockdown of RhoA expression rescued the effects of miR-340 inhibition on SCC cell proliferation, migration and invasion. More importantly, the expression of RhoA and miR-340 was negatively correlated in SCC tissues. CONCLUSION Our findings demonstrate the tumor suppressor role of miR-340 in SCC by directly regulating RhoA. Therefore, restoration of miR-340 expression can be a potential therapeutic approach for SCC treatment.