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ALKBH5-Mediated m6A Modification of XBP1 Facilitates NSCLC Progression Through the IL-6-JAK-STAT3 Pathway. ALKBH5 介导的 XBP1 m6A 修饰通过 IL-6-JAK-STAT3 通路促进 NSCLC 进展
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-10 DOI: 10.1002/mc.23826
Hengxing Liang, Chunmin Zhang, Minxin Hu, Fang Hu, Saihui Wang, Wei Wei, Wen Hu

The X-box-binding protein 1 (XBP1) is an important transcription factor during endoplasmic reticulum stress response, which was reported as an oncogene in non-small cell lung cancer (NSCLC) tumorigenesis and development. However, the regulatory mechanism of XBP1 expression in NSCLC progression was less reported. N6-methyladenosine (m6A) RNA modification is an emerging epigenetic regulatory mechanism for gene expression. This study aimed to investigate the regulatory role of the m6A modification in XBP1 expression in NSCLC. We identified XBP1 as a downstream target of ALKBH5-mediated m6A modification in A549 and PC9 cells. Knockdown of ALKBH5 increased the m6A modification and the stability of XBP1 mRNA, while overexpression of ALKBH5 had the opposite effect. Furthermore, IGF2BP3 was confirmed to be a reader of XBP1 m6A methylation and to enhance the stability of XBP1 mRNA. Additionally, IGF2BP3 knockdown significantly reversed the increase in XBP1 stability mediated by ALKBH5 depletion. In vivo and in vitro experiments demonstrated that ALKBH5/IGF2BP3 promotes the proliferation, migration, and invasion of NSCLC cells by upregulating XBP1 expression. In addition, we also showed that XBP1 promoted NSCLC cell proliferation, migration, and invasion by activating IL-6-JAK-STAT3 signaling. Our research suggested that ALKBH5-mediated m6A modification of XBP1 facilitates NSCLC progression through the IL-6-JAK-STAT3 pathway.

X-box 结合蛋白 1(XBP1)是内质网应激反应过程中的一个重要转录因子,有报道称它是非小细胞肺癌(NSCLC)肿瘤发生和发展过程中的一个癌基因。然而,XBP1在NSCLC进展过程中的表达调控机制却鲜有报道。N6-甲基腺苷(m6A)RNA修饰是一种新兴的基因表达表观遗传调控机制。本研究旨在探讨 m6A 修饰在 NSCLC 中 XBP1 表达中的调控作用。我们发现XBP1是ALKBH5介导的m6A修饰在A549和PC9细胞中的下游靶点。敲除 ALKBH5 会增加 m6A 修饰和 XBP1 mRNA 的稳定性,而过表达 ALKBH5 则会产生相反的效果。此外,IGF2BP3 被证实是 XBP1 m6A 甲基化的阅读器,并能增强 XBP1 mRNA 的稳定性。此外,敲除 IGF2BP3 能显著逆转 ALKBH5 缺失所介导的 XBP1 稳定性的增加。体内和体外实验证明,ALKBH5/IGF2BP3通过上调XBP1的表达促进了NSCLC细胞的增殖、迁移和侵袭。此外,我们还发现 XBP1 通过激活 IL-6-JAK-STAT3 信号促进 NSCLC 细胞的增殖、迁移和侵袭。我们的研究表明,ALKBH5 介导的 XBP1 m6A 修饰通过 IL-6-JAK-STAT3 通路促进了 NSCLC 的进展。
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引用次数: 0
Silmitasertib in Combination With Cabozantinib Impairs Liver Cancer Cell Cycle Progression, Induces Apoptosis, and Delays Tumor Growth in a Preclinical Model. 在临床前模型中,Silmitasertib与Cabozantinib联用可抑制肝癌细胞周期进展、诱导细胞凋亡并延缓肿瘤生长。
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-08 DOI: 10.1002/mc.23827
Yuki Haga, Ranjit Ray, Ratna B Ray

The rising incidence of hepatocellular carcinoma (HCC) is a global problem. Several approved treatments, including immune therapy and multi-tyrosine kinase inhibitors, are used for treatment, although the results are not optimum. There is an unmet need to develop highly effective chemotherapies for HCC. Targeting multiple pathways to attack cancer cells is beneficial. Cabozantinib is an orally available bioactive multikinase inhibitor and has a modest effect on HCC treatment. Silmitasertib is an orally bioavailable, potent CK2 inhibitor with a direct role in DNA damage repair and is in clinical trials for other cancers. In this study, we planned to repurpose these existing drugs on HCC treatment. We observed a stronger antiproliferative effect of these two combined drugs on HCC cells generated from different etiologies as compared to the single treatment. Global RNA-seq analyses revealed a decrease in the expression of G2/M cell cycle transition genes in HCC cells following combination treatment, suggesting G2 phase cell arrest. We observed G2/M cell cycle phase arrest in HCC cells upon combination treatment compared to the single-treated or vehicle-treated control cells. The downregulation of CCNA2 and CDC25C following combination therapy further supported the observation. Subsequent analyses demonstrated that combination treatment inhibited 70 kDa ribosomal protein S6 kinase (p70S6K) phosphorylation, and increased Bim expression. Apoptosis of HCC cells were accompanied by increased poly (ADP-ribose) polymerase cleavage and caspase-9 activation. Next, we observed that a combination therapy significantly delayed the progression of HCC xenograft growth as compared to vehicle control. Together, our results suggested combining cabozantinib and silmitasertib would be a promising treatment option for HCC.

肝细胞癌(HCC)发病率的上升是一个全球性问题。目前,包括免疫疗法和多酪氨酸激酶抑制剂在内的几种已获批准的疗法被用于治疗,但效果并不理想。针对 HCC 开发高效化学疗法的需求尚未得到满足。靶向多种途径攻击癌细胞是有益的。Cabozantinib 是一种口服生物活性多激酶抑制剂,对治疗 HCC 有一定效果。Silmitasertib是一种口服生物活性强的CK2抑制剂,直接作用于DNA损伤修复,目前正在进行其他癌症的临床试验。在本研究中,我们计划将这些现有药物重新用于治疗 HCC。与单一治疗相比,我们观察到这两种药物联合使用对不同病因产生的 HCC 细胞有更强的抗增殖作用。全局 RNA-seq 分析显示,联合用药治疗后,HCC 细胞中 G2/M 细胞周期转换基因的表达量减少,这表明 G2 期细胞停滞。与单一治疗或药物治疗的对照细胞相比,我们观察到联合治疗后 HCC 细胞的 G2/M 细胞周期停滞。联合治疗后 CCNA2 和 CDC25C 的下调进一步证实了这一观察结果。随后的分析表明,联合疗法抑制了 70 kDa 核糖体蛋白 S6 激酶(p70S6K)的磷酸化,并增加了 Bim 的表达。HCC细胞的凋亡伴随着多(ADP-核糖)聚合酶裂解和Caspase-9活化的增加。接下来,我们观察到,与药物对照组相比,联合疗法明显延缓了 HCC 异种移植的生长进程。总之,我们的研究结果表明,将卡博替尼和司米他替尼联合治疗HCC将是一种很有前景的治疗方案。
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引用次数: 0
AKAP95 regulates ubiquitination and degradation of cyclin Ds/Es, influencing the G1/S transition of lung cancer cells. AKAP95 可调节细胞周期蛋白 Ds/Es 的泛素化和降解,从而影响肺癌细胞的 G1/S 转换。
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-01 Epub Date: 2024-06-24 DOI: 10.1002/mc.23781
Zifeng Deng, Liangding Dou, Zhen Luo, Rong Liu, Jinwen Zhang, Jing Wang, Dai Wang, DongBei Guo, Ran An, Youliang Yao, Guihua Qiu, Yongxing Zhang

A-kinase anchoring protein 95 (AKAP95) functions as a scaffold for protein kinase A. Prior work by our group has shown that AKAP95, in coordination with Connexin 43 (Cx43), modulates the expression of cyclin D and E proteins, thus affecting the cell cycle progression in lung cancer cells. In the current study, we confirmed that AKAP95 forms a complex with Cx43. Moreover, it associates with cyclins D1 and E1 during the G1 phase, leading to the formation of protein complexes that subsequently translocate to the nucleus. These findings indicate that AKAP95 might facilitate the nuclear transport of cyclins D1 and E1. Throughout this process, AKAP95 and Cx43 collectively regulate the expression of cyclin D, phosphorylate cyclin E1 proteins, and target their specific ubiquitin ligases, ultimately impacting cell cycle progression.

A 激酶锚定蛋白 95(AKAP95)是蛋白激酶 A 的支架。我们小组之前的研究表明,AKAP95 与连接蛋白 43(Cx43)协同调节细胞周期蛋白 D 和 E 的表达,从而影响肺癌细胞的细胞周期进程。在本研究中,我们证实了 AKAP95 与 Cx43 形成复合物。此外,它还在 G1 期与细胞周期蛋白 D1 和 E1 结合,形成蛋白复合物,随后转运至细胞核。这些发现表明,AKAP95 可能会促进细胞周期蛋白 D1 和 E1 的核转运。在整个过程中,AKAP95和Cx43共同调节细胞周期蛋白D的表达,使细胞周期蛋白E1蛋白磷酸化,并靶向其特定的泛素连接酶,最终影响细胞周期的进展。
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引用次数: 0
Latrophilin-3 as a downstream effector of the androgen receptor induces urothelial tumorigenesis. Latrophilin-3作为雄激素受体的下游效应因子诱导尿道肿瘤发生。
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-01 Epub Date: 2024-06-24 DOI: 10.1002/mc.23783
Takuro Goto, Masato Yasui, Yuki Teramoto, Yujiro Nagata, Taichi Mizushima, Hiroshi Miyamoto

Emerging evidence indicates that androgen receptor (AR) signaling plays a critical role in the pathogenesis of male-dominant urothelial cancer. Meanwhile, latrophilins (LPHNs), a group of the G-protein-coupled receptor to which a spider venom latrotoxin is known to bind, remain largely uncharacterized in neoplastic diseases. The present study aimed to determine the functional role of LPHN3 (encoded by the ADGRL3 gene), in association with AR signaling, in urothelial tumorigenesis. In human normal urothelial SVHUC cells, AR overexpression and androgen treatment considerably increased the expression levels of ADGRL3/LPHN3, while chromatin immunoprecipitation assay revealed the binding of AR to the promoter region of ADGRL3. In SVHUC or SVHUC-AR cells with exposure to a chemical carcinogen 3-methylcholanthrene, LPHN3 activation via ligand (e.g., α-latrotoxin, FLRT3) treatment during the process of the neoplastic/malignant transformation or LPHN3 knockdown via shRNA virus infection induced or reduced, respectively, the oncogenic activity. In N-butyl-N-(4-hydroxybutyl)nitrosamine-treated female mice, α-latrotoxin or FLRT3 injection accelerated the development of bladder tumors. Immunohistochemistry in surgical specimens further showed the significantly elevated expression of LPHN3 in non-muscle-invasive bladder tumors, compared with adjacent normal urothelial tissues, which was associated with a marginally (p = 0.051) higher risk of disease recurrence after transurethral resection. In addition, positivity of LPHN3 and AR in these tumors was strongly correlated. These findings indicate that LPHN3 functions as a downstream effector of AR and promotes urothelial tumorigenesis.

新的证据表明,雄激素受体(AR)信号在男性占主导地位的尿道癌的发病机制中起着至关重要的作用。与此同时,已知与蜘蛛毒液潜伏毒素结合的一组G蛋白偶联受体--潜伏嗜神经蛋白(LPHNs)在肿瘤性疾病中的作用在很大程度上仍未定性。本研究旨在确定 LPHN3(由 ADGRL3 基因编码)与 AR 信号在尿道肿瘤发生中的功能作用。在人正常尿道SVHUC细胞中,AR过表达和雄激素治疗显著增加了ADGRL3/LPHN3的表达水平,染色质免疫沉淀检测发现AR与ADGRL3的启动子区域结合。在暴露于化学致癌物3-甲基胆蒽的SVHUC或SVHUC-AR细胞中,在肿瘤/恶性转化过程中通过配体(如α-脂肪毒素、FLRT3)处理激活LPHN3,或通过shRNA病毒感染敲除LPHN3,分别诱导或降低了致癌活性。在N-丁基-N-(4-羟基丁基)亚硝胺处理的雌性小鼠中,注射α-莱托毒素或FLRT3会加速膀胱肿瘤的发展。手术标本的免疫组化进一步显示,与邻近的正常尿路组织相比,非肌层浸润性膀胱肿瘤中 LPHN3 的表达明显升高,这与经尿道切除术后疾病复发风险略高(p = 0.051)有关。此外,LPHN3和AR在这些肿瘤中的阳性率密切相关。这些研究结果表明,LPHN3是AR的下游效应因子,促进了尿路肿瘤的发生。
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引用次数: 0
UBE2D1 promotes glioblastoma proliferation by modulating p21 ubiquitination. UBE2D1 通过调节 p21 泛素化促进胶质母细胞瘤增殖。
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-01 Epub Date: 2024-07-17 DOI: 10.1002/mc.23786
Yongfeng Wang, Qianquan Ma, Haoyu Li, Wei Huang, Jia You, Dian Liu

Glioblastoma (GBM) cells exhibit aberrant proliferative abilities and resistance to conventional therapies. However, the mechanisms underlying these malignant phenotypes are poorly understood. In this study, we identified ubiquitin-conjugating enzyme E2D1 (UBE2D1) as a crucial stimulator of GBM development. It is highly expressed in GBM and closely associated with poor prognosis in patients with GBM. UBE2D1 knockdown inhibits GBM cell growth and leads to G1 cell cycle arrest. Mechanistically, UBCH5A binds to p21 at the protein level and induces the ubiquitination and degradation of p21. This negative regulation is mediated by STUB1. Our findings are the first to identify UBE2D1 as a key driver of GBM growth and provide a potential target for improving prognosis and therapy.

胶质母细胞瘤(GBM)细胞表现出异常的增殖能力和对传统疗法的抵抗力。然而,人们对这些恶性表型的机制知之甚少。在这项研究中,我们发现泛素结合酶 E2D1(UBE2D1)是 GBM 发育的关键刺激因子。它在 GBM 中高表达,与 GBM 患者的不良预后密切相关。敲除 UBE2D1 可抑制 GBM 细胞生长并导致 G1 细胞周期停滞。从机理上讲,UBCH5A 在蛋白水平上与 p21 结合,诱导 p21 泛素化和降解。这种负调控是由 STUB1 介导的。我们的发现首次确定了 UBE2D1 是 GBM 生长的关键驱动因素,并为改善预后和治疗提供了潜在靶点。
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引用次数: 0
Methylation, Gene Expression, and Risk Genotypes at the TERT-CLPTM1L Locus in Cervical Cancer. 宫颈癌中 TERT-CLPTM1L 基因座的甲基化、基因表达和风险基因型。
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-01 DOI: 10.1002/mc.23822
Dhanya Ramachandran, Qianqian Mao, Dandan Liao, Maud Kamal, Peter Schürmann, Rieke Eisenblätter, Robert Geffers, Balazs Balint, Lolita Lecompte, Nicolas Servant, Linda Larbi Chérif, Constance Lamy, Sylvain Baulande, Patricia Legoix, Christophe Le Tourneau, Aurélien Latouche, Peter Hillemanns, Suzy Scholl, Thilo Dörk

The reverse transcriptase subunit of telomerase, TERT, is frequently activated in high-grade dysplasia and invasive cancers of the uterine cervix. Telomerase activation through hypomethylation of the TERT promoter holds promise as a biomarker for cervical cancer progression, however, specific CpG sites involved in cervical cancer risk remain to be fully defined. A recent genome-wide association study on cervical cancer identified genetic polymorphisms at 5p13.33 (close to TERT-CLPTM1L) but the underlying mechanisms are undetermined. We investigated 529 CpG sites within the TERT promoter region and 3 CpG islands nearby, and 21 CpG sites within CLPTM1L in 190 bisulfite-converted cervical tumor DNA samples from BioRAIDs (NCT02428842). We identified eight CpG sites within TERT intron 2 where methylation was significantly associated with the genotypes of cervical cancer risk variants rs27070 and rs459961 in cervical tumors after multiple testing correction (p < 9.4 × 10E-5). Hypermethylation at chr5:1289663 correlated with decreased TERT mRNA levels. In an independent series of 188 normal or dysplastic cervical tissues, rare alleles of rs27070 and rs459961 were associated with low basal CLPTM1L levels and with the absence of TERT mRNA in HPV-negative samples, consistent with their proposed role as protective variants for cervical cancer. HPV infection was associated with increased CLPTM1L and TERT levels. Collectively, our results provide a link between cervical cancer risk variants, methylation, and gene expression and implicate both TERT and CLPTM1L as genes modulated by genomic background and HPV infection during cervical cancer development.

端粒酶的逆转录酶亚基 TERT 经常在宫颈高度发育不良和浸润性癌症中被激活。通过 TERT 启动子的低甲基化激活端粒酶有望成为宫颈癌进展的生物标志物,然而,与宫颈癌风险有关的特定 CpG 位点仍有待完全确定。最近一项关于宫颈癌的全基因组关联研究发现了 5p13.33(靠近 TERT-CLPTM1L)的基因多态性,但其潜在机制尚未确定。我们在 BioRAIDs (NCT02428842) 的 190 份经亚硫酸氢盐转化的宫颈肿瘤 DNA 样本中调查了 TERT 启动子区域内的 529 个 CpG 位点和附近的 3 个 CpG 岛,以及 CLPTM1L 内的 21 个 CpG 位点。我们在 TERT 内含子 2 中发现了 8 个 CpG 位点,经多重检验校正后,这些位点的甲基化与宫颈癌风险变异 rs27070 和 rs459961 的基因型显著相关(p
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引用次数: 0
Frizzled 6 endows high-grade serous ovarian cancer with stem-like properties and chemoresistance. Frizzled 6赋予高级别浆液性卵巢癌干样特性和化疗抗性。
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-01 Epub Date: 2024-08-12 DOI: 10.1002/mc.23789
Shaorong Chen, Guang Yang, Qirong Shi, Ningning Wan, Ruyin Lin, Lianhua Wang, Xinxin Hu, Xuanxuan Zhuang, Liying Yu, Ming Sui

Stem-like properties contribute to tumor growth, metastasis, and chemoresistance. High-grade serous ovarian cancer (HGSOC) exhibits a very aggressive phenotype characterized by extensive metastasis, rapid progression, and therapy resistance. Frizzled 6 (FZD6) is overexpressed in HGSOC, and higher levels of FZD6 have been associated with shorter survival times in patients with HGSOC. Functionally, FZD6 promotes HGSOC growth and peritoneal metastasis. It endues HGSOC cells with stem-like properties by modulating POU5F1, ALDH1, and EPCAM. It can also desensitize HGSOC cells to certain chemical drugs. As a putative ligand for FZD6, WNT7B is also implicated in cell proliferation, stem-like properties, invasion and migration, and chemoresistance. SMAD7 is a downstream component of FZD6 signaling that is thought to mediate FZD6-associated phenotypes, at least in part. Therefore, FZD6/WNT7B-SMAD7 can be considered a tumor-promoting signaling pathway in HGSOC that may be responsible for tumor growth, peritoneal metastasis, and chemoresistance.

干样特性有助于肿瘤生长、转移和耐药性。高分化浆液性卵巢癌(HGSOC)具有侵袭性很强的表型,其特点是广泛转移、进展迅速和耐药。Frizzled 6(FZD6)在 HGSOC 中过表达,较高水平的 FZD6 与 HGSOC 患者较短的生存时间有关。在功能上,FZD6 能促进 HGSOC 的生长和腹膜转移。它通过调节 POU5F1、ALDH1 和 EPCAM 使 HGSOC 细胞具有干样特性。它还能使 HGSOC 细胞对某些化学药物脱敏。作为 FZD6 的配体,WNT7B 还与细胞增殖、干样特性、侵袭和迁移以及化疗抗性有关。SMAD7 是 FZD6 信号传导的下游成分,被认为至少部分介导了 FZD6 相关表型。因此,FZD6/WNT7B-SMAD7 可被视为 HGSOC 中的一种肿瘤促进信号通路,可能是肿瘤生长、腹膜转移和化疗耐药性的罪魁祸首。
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引用次数: 0
YAP-LAMB3 axis dictates cellular resistance of pancreatic ductal adenocarcinoma cells to gemcitabine. YAP-LAMB3 轴决定了胰腺导管腺癌细胞对吉西他滨的耐药性。
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-01 Epub Date: 2024-07-17 DOI: 10.1002/mc.23785
Yecheng Li, Xiaolong Wang, Hongpei Yu, Jinming Cao, Jiaming Xie, Jinhong Zhou, Zhenyu Feng, Wei Chen

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumors with poor prognosis and inadequate response to treatment, such as gemcitabine (Gem), the first-line chemotherapeutic drug. Understanding the molecular determinants that control drug resistance to Gem is critical to predict potentially responsive patients and improve the benefits of Gem therapy. Emerging evidence suggests that certain developmental pathways, such as Hippo signaling, are aberrated and play important roles in Gem resistance in cancers. Although Hippo signaling has been reported to play a role in chemoresistance in cancers, it has not been clarified which specific target gene(s) functionally mediates the effect. In the present study, we found that YAP serves as a potent barrier for the cellular sensitivity of PDAC cells to Gem. We then identified and characterized laminin subunit beta 3 (LAMB3) as a bona fide target of YAP-TEAD4 to amplify YAP signaling via a feedback loop. Such a YAP-LAMB3 axis is critical to induce epithelial-mesenchymal transition and mediate Gem resistance. Taken together, we uncovered that YAP-LAMB3 axis is an important regulator of Gem, thus providing potential therapeutic targets for overcoming Gem resistance in PDAC.

胰腺导管腺癌(PDAC)是侵袭性最强的肿瘤之一,预后不良,对吉西他滨(Gem)等一线化疗药物的反应不佳。了解控制吉西他滨耐药性的分子决定因素对于预测潜在反应患者和提高吉西他滨疗法的疗效至关重要。新的证据表明,某些发育途径(如 Hippo 信号转导)发生了异常,并在癌症的 Gem 抗药性中发挥了重要作用。虽然有报道称 Hippo 信号在癌症化疗耐药性中起作用,但尚未明确是哪种特定的靶基因在功能上介导了这种效应。在本研究中,我们发现 YAP 是 PDAC 细胞对 Gem 敏感性的有效屏障。然后,我们发现并鉴定了层粘连蛋白亚基 beta 3(LAMB3),它是 YAP-TEAD4 的真正靶标,可通过反馈环路放大 YAP 信号。这种 YAP-LAMB3 轴对于诱导上皮-间充质转化和介导 Gem 抗性至关重要。综上所述,我们发现 YAP-LAMB3 轴是 Gem 的一个重要调节因子,从而为克服 PDAC 的 Gem 抗性提供了潜在的治疗靶点。
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引用次数: 0
C5AR1-induced TLR1/2 pathway activation drives proliferation and metastasis in anaplastic thyroid cancer. C5AR1诱导的TLR1/2通路活化推动了无性甲状腺癌的增殖和转移。
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-01 Epub Date: 2024-06-27 DOI: 10.1002/mc.23784
Bo Liu, Yueyao Sun, Tongyao Geng, Haobo Wang, Zhenyu Wu, Lei Xu, Miao Zhang, Xupeng Niu, Chenxu Zhao, Jin Shang, Fangjian Shang

This study aimed to elucidate the role and mechanisms of Complement C5a receptor 1 (C5AR1) in driving the malignant progression of anaplastic thyroid carcinoma (ATC). C5AR1 expression was assessed in ATC tissues and cell lines. Functional assays evaluated the effects of C5AR1 knockdown on the malignant features of ATC cells. The interaction between C5AR1 and miR-335-5p was confirmed using a luciferase reporter assay and Fluorescence in situ hybridization, and the impact of C5AR1 knockdown on the Toll-like receptor (TLR) 1/2 signaling pathway was examined. In vivo studies evaluated the effects of C5AR1 modulation on tumor growth and metastasis. C5AR1 levels were elevated in ATC tumor samples and associated with poor survival in ATC patients. C5AR1 knockdown impeded ATC cell proliferation, migration, and invasion in vitro. MiR-335-5p was identified as an upstream regulator of C5AR1, which negatively modulates C5AR1 expression. C5AR1 knockdown diminished TLR1, TLR2, and myeloid differentiation primary response 88 (MyD88) levels, while C5AR1 overexpression activated this pathway. Blocking TLR1/2 signaling abrogated the oncogenic effects of C5AR1 overexpression. C5AR1 silencing inhibited tumor growth and lung metastasis of ATC cells in nude mice. C5AR1 contributes to ATC tumorigenesis and metastasis by activating the TLR1/2 pathway, and is negatively regulated by miR-335-5p. Targeting the miR-335-5p/C5AR1/TLR1/2 axis represents a potential therapeutic strategy for ATC.

本研究旨在阐明补体C5a受体1(C5AR1)在推动无性甲状腺癌(ATC)恶性进展中的作用和机制。评估了C5AR1在ATC组织和细胞系中的表达。功能测定评估了 C5AR1 敲除对 ATC 细胞恶性特征的影响。荧光素酶报告实验和荧光原位杂交证实了C5AR1和miR-335-5p之间的相互作用,并考察了C5AR1敲除对Toll样受体(TLR)1/2信号通路的影响。体内研究评估了 C5AR1 调节对肿瘤生长和转移的影响。C5AR1水平在ATC肿瘤样本中升高,并与ATC患者生存率低有关。体外敲除 C5AR1 会阻碍 ATC 细胞的增殖、迁移和侵袭。研究发现,MiR-335-5p是C5AR1的上游调节因子,它能负向调节C5AR1的表达。C5AR1敲除会降低TLR1、TLR2和髓样体分化初级反应88(MyD88)的水平,而C5AR1过表达则会激活这一通路。阻断TLR1/2信号传导可减轻C5AR1过表达的致癌作用。C5AR1沉默抑制了裸鼠ATC细胞的肿瘤生长和肺转移。C5AR1通过激活TLR1/2通路促进ATC肿瘤发生和转移,并受到miR-335-5p的负调控。靶向 miR-335-5p/C5AR1/TLR1/2 轴是一种潜在的 ATC 治疗策略。
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引用次数: 0
The role of immune checkpoint inhibitors: Variable number of tandem repeat (VNTR) polymorphism in the second exon of the P-selectin glycoprotein ligand-1 (PSGL-1) gene polymorphism in multiple myeloma. 免疫检查点抑制剂的作用:多发性骨髓瘤中P-选择素糖蛋白配体-1(PSGL-1)基因第二外显子多态性的串联重复变异数(VNTR)。
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-01 Epub Date: 2024-07-02 DOI: 10.1002/mc.23787
Yasemin Oyaci, Mustafa Pehlivan, Sacide Pehlivan, Tahir Alper Cinli, Fatima Ceren Tuncel, Elif Ertas, Istemi Serin

Somatic mutations and polymorphisms may play a role in multiple myeloma (MM) susceptibility and survival. One of the immune checkpoint inhibitors is P-selectin glycoprotein ligand-1 (PSGL-1); the majority of tumor-infiltrating leukocytes express PSGL-1, causing T cell and immune inhibition via PSGL-1 mediator molecules. We aimed to investigate the effect of variable number of tandem repeat (VNTR) polymorphism in the second exon of the PSGL-1 gene on MM susceptibility, response to treatment and survival in our patient group. A total of 238 patients diagnosed with MM between January 2010 and January 2021 and 162 healthy individuals as a control group were included in this cross-sectional study. The genotypes of the VNTR polymorphism in the second exon of the PSGL-1 gene were statistically compared between patients and healthy controls; the statistically significant effects of the genotypes on response to first-line treatment and survival were examined. The AC genotype was significantly higher in healthy controls compared to patients diagnosed with MM (p < 0.001). The median PFS in patients with AA/AB/AC was 56 months, while it was 100 months in patients with BB/CC. The hazard ratio of 1.34 for PFS was found to be clinically significant and having the BB/CC genotype could provide a longer PFS compared to others, but it was not statistically significant due to the sample size. Our study results will shed light on new study plans in terms of immune checkpoint target therapies among conventional treatment preferences in MM.

体细胞突变和多态性可能对多发性骨髓瘤(MM)的易感性和存活率有影响。免疫检查点抑制剂之一是P-选择素糖蛋白配体-1(PSGL-1);大多数肿瘤浸润白细胞表达PSGL-1,通过PSGL-1介导分子导致T细胞和免疫抑制。我们的目的是研究 PSGL-1 基因第二外显子的可变串联重复数(VNTR)多态性对 MM 易感性、治疗反应和患者生存期的影响。这项横断面研究共纳入了238名在2010年1月至2021年1月期间确诊为MM的患者和162名健康人作为对照组。统计比较了患者和健康对照组之间PSGL-1基因第二外显子VNTR多态性的基因型,并考察了基因型对一线治疗反应和生存期的显著影响。与确诊为 MM 的患者相比,健康对照组的 AC 基因型明显较高(p
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引用次数: 0
期刊
Molecular Carcinogenesis
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