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Knockdown of PAIP1 Inhibits Breast Cancer Cell Proliferation by Regulating Cyclin E2 mRNA Stability 敲除 PAIP1 可通过调节 Cyclin E2 mRNA 稳定性抑制乳腺癌细胞增殖
IF 4.6 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-11 DOI: 10.1002/mc.23817
Wenqing Yang, Qingkun Wang, Qi Li, Yue Han, Yu Zhang, Lu Zhu, Lianhua Zhu, Junjie Piao
Polyadenylate‐binding protein‐interacting protein 1 (PAIP1) is a protein that modulates translation initiation in eukaryotic cells. Studies have shown that PAIP1 was overexpressed in various type of cancers, and drives cancer progression by promoting cancer cell proliferation, invasion, and migration. In our previous study, we identified that PAIP1 was overexpressed in breast cancer, and the expression was correlated with poor prognosis. However, the biological function of PAIP1 in breast cancer has not been clearly understood. In this study, we constructed PAIP1 specifically silenced breast cancer cells. Then, cell proliferation, cell cycle distribution, and apoptosis were detected in PAIP1 knockdown cells. RNA‐seq analysis was performed to predict the downstream target of PAIP1, and the molecular mechanism was explored. As a results, we found that knockdown of PAIP1 repressed cell proliferation, induced cell cycle arrest, and triggers apoptosis. Xenograft mouse model showed that knockdown of PAIP1 inhibits cell growth in vivo. RNA‐seq predicted that CCNE2 mRNA was one of the downstream targets of PAIP1. In addition, we identified that knockdown of PAIP1‐inhibited cell proliferation through modulating cyclin E2 expression. Mechanically, knockdown of PAIP1 reduces the expression of cyclin E2 by regulating the mRNA stability of cyclin E2. Moreover, in breast cancer tissues, we found that the expression of PAIP1 was positively correlated with cyclin E2. Taken together, our findings establish the role and mechanism of PAIP1 in breast cancer progression, indicating that PAIP1 would be a new therapeutic target for breast cancer treatment.
多聚腺苷酸结合蛋白相互作用蛋白 1(PAIP1)是一种调节真核细胞翻译起始的蛋白。研究表明,PAIP1 在多种癌症中过表达,并通过促进癌细胞增殖、侵袭和迁移来推动癌症进展。在我们之前的研究中,我们发现 PAIP1 在乳腺癌中过表达,并且其表达与不良预后相关。然而,PAIP1 在乳腺癌中的生物学功能尚不清楚。在本研究中,我们构建了特异性沉默 PAIP1 的乳腺癌细胞。然后,检测了 PAIP1 敲除细胞的细胞增殖、细胞周期分布和细胞凋亡。通过RNA-seq分析预测了PAIP1的下游靶标,并探讨了其分子机制。结果发现,敲除 PAIP1 可抑制细胞增殖、诱导细胞周期停滞并引发细胞凋亡。异种移植小鼠模型显示,敲除 PAIP1 可抑制体内细胞生长。RNA-seq预测CCNE2 mRNA是PAIP1的下游靶标之一。此外,我们还发现,敲除 PAIP1 可通过调节细胞周期蛋白 E2 的表达来抑制细胞增殖。从机理上讲,敲除 PAIP1 通过调节细胞周期蛋白 E2 的 mRNA 稳定性来降低细胞周期蛋白 E2 的表达。此外,在乳腺癌组织中,我们发现 PAIP1 的表达与细胞周期蛋白 E2 呈正相关。综上所述,我们的研究结果确定了 PAIP1 在乳腺癌进展中的作用和机制,表明 PAIP1 将成为乳腺癌治疗的新靶点。
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引用次数: 0
Monoubiquitinated H2B, a Main Chromatin Target of Formaldehyde, Is Important for S‐Phase Checkpoint Signaling and Genome Stability 单泛素化的 H2B 是甲醛的主要染色质靶标,对 S 期检查点信号传导和基因组稳定性非常重要
IF 4.6 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-10 DOI: 10.1002/mc.23819
Sasmita Mishra, Casey Krawic, Michal W. Luczak, Anatoly Zhitkovich
Formaldehyde (FA) is a human carcinogen with ubiquitous environmental exposures and significant endogenous formation. Genotoxic activity of FA stems from its reactivity with DNA‐NH2 groups. Histone lysines are another source of aldehyde‐reactive amino groups in chromatin, however, chromatin/histone damage responses to FA and their biological significance are poorly understood. We examined histone posttranslational modifications in FA‐treated human lung cells and found that the majority of the most prominent small lysine modifications associated with active or inactive chromatin were unchanged. FA moderately decreased H3K9 and H3K27 acetylation and H2A‐K119 monoubiquitination but caused surprisingly severe losses of H2B‐K120 monoubiquitination, especially in primary and stem‐like cells. H2Aub1 decreases reflected its slower ubiquitination linked to a lower ubiquitin availability due to K48‐polyubiquitination of FA‐damaged proteins. Depletion of H2Bub1 resulted from its rapid deubiquitination in part by ATXN7L3‐associated deubiquitinases and was independent on DNA damage signaling, indicating a direct chromatin damage response. Manipulations of H2Bub1 abundance showed that it was important for robust ATM and ATR signaling, efficient S‐phase checkpoint, and suppression of mitotic transmission of unreplicated DNA and formation of micronuclei. Our findings identified H2B deubiquitination as a major FA‐induced chromatin damage response that regulates S‐phase checkpoint signaling and genome stability.
甲醛(FA)是一种人类致癌物质,环境中的接触无处不在,而且在体内也会形成大量甲醛。甲醛的基因毒性源于它与 DNA-NH2 基团的反应性。组蛋白赖氨酸是染色质中醛反应性氨基的另一个来源,然而,人们对染色质/组蛋白对 FA 的损伤反应及其生物学意义还知之甚少。我们研究了经 FA 处理的人肺细胞中的组蛋白翻译后修饰,发现与活跃或不活跃染色质相关的大多数最突出的小赖氨酸修饰均保持不变。FA适度降低了H3K9和H3K27乙酰化以及H2A-K119单泛素化,但却导致H2B-K120单泛素化的惊人严重损失,尤其是在原代细胞和干样细胞中。H2Aub1的减少反映了其泛素化速度较慢,这与FA损伤蛋白的K48-多泛素化导致泛素可用性降低有关。H2Bub1的耗竭部分是由于其被ATXN7L3相关的去泛素化酶快速去泛素化,而且与DNA损伤信号无关,这表明这是一种直接的染色质损伤反应。对H2Bub1丰度的控制表明,它对ATM和ATR信号的稳健、S期检查点的高效、抑制有丝分裂期未复制DNA的传递和微核的形成非常重要。我们的研究结果确定了H2B去泛素化是FA诱导的主要染色质损伤反应,可调节S期检查点信号传导和基因组稳定性。
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引用次数: 0
Adipocytes Promote Endometrial Cancer Progression Through Activation of the SIRT1‐HMMR Signaling Axis 脂肪细胞通过激活 SIRT1-HMMR 信号轴促进子宫内膜癌进展
IF 4.6 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-10 DOI: 10.1002/mc.23815
Akanksha Savardekar, Ellerhea Fernandes, Aishwarya Padhye‐Pendse, Tanish Gupta, Jaydeep Pol, Madhura Phadke, Sharad Desai, Sachin Jadhav, Jyutika Rajwade, Arnab Banerjee
Adipocyte is a predominant component of the omental adipose tissue that influences the tumor microenvironment and increases the risk of endometrial cancer progression (EC), however, little is known about the underlying mechanism. In this study, using a co‐culture model, we found that the adipocyte‐EC cell interaction promoted SIRT1 signaling in vitro and in vivo xenograft mice models. Furthermore, immunostaining of SIRT1 protein showed significantly higher expression of SIRT1 in endometrial cancer patients than in normal endometria. RNA sequencing analysis revealed HMMR (hyaluronan‐mediated motility receptor), an oncogene, as a downstream effector of SIRT1 in adipocyte‐associated EC. Transient knockdown and chromatin immunoprecipitation assays showed that SIRT1 inhibition impedes transcription of the HMMR gene via FOXM1, and reduced expression of HMMR in co‐cultured EC cells blocks AURKA activation via TPX2, leading to cell cycle arrest. This is the first study to report the positive correlation between SIRT1 and HMMR in EC patient tumors and might be used as a potential biomarker in EC. Notably, SIRT1 regulates HMMR expression in a FOXM1‐dependent manner, and interfering with SIRT1 may provide a promising strategy for the management of endometrial cancer.
脂肪细胞是网膜脂肪组织的主要成分,它会影响肿瘤微环境并增加子宫内膜癌(EC)进展的风险,然而,人们对其潜在机制知之甚少。在这项研究中,我们利用共培养模型发现,脂肪细胞-EC 细胞相互作用促进了体外和体内异种移植小鼠模型中的 SIRT1 信号转导。此外,SIRT1 蛋白的免疫染色显示,子宫内膜癌患者体内 SIRT1 的表达明显高于正常子宫内膜。RNA测序分析表明,在脂肪细胞相关的EC中,癌基因HMMR(透明质酸介导的运动受体)是SIRT1的下游效应因子。瞬时基因敲除和染色质免疫共沉淀试验表明,抑制 SIRT1 会通过 FOXM1 阻碍 HMMR 基因的转录,而在共培养的 EC 细胞中减少 HMMR 的表达会通过 TPX2 阻碍 AURKA 的激活,从而导致细胞周期停滞。这是首次报道SIRT1和HMMR在EC患者肿瘤中的正相关性,可作为EC的潜在生物标志物。值得注意的是,SIRT1以一种依赖于FOXM1的方式调控HMMR的表达,干扰SIRT1可能会为子宫内膜癌的治疗提供一种有前景的策略。
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引用次数: 0
ADAR1 Promotes Invasion and Migration and Inhibits Ferroptosis via the FAK/AKT Pathway in Colorectal Cancer. ADAR1 通过 FAK/AKT 通路促进结直肠癌的侵袭和迁移并抑制铁凋亡
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-06 DOI: 10.1002/mc.23818
Dongsheng He, Chao Niu, Rilan Bai, Naifei Chen, Jiuwei Cui

The role of adenosine deaminase acting on RNA1 (ADAR1) in colorectal cancer (CRC) is poorly understood. This study investigated the roles and underlying molecular mechanisms of ADAR1 and its isoforms, explored the correlations between ADAR1 expression and the immune microenvironment and anticancer drug sensitivity, and examined the potential synergy of using ADAR1 expression and clinical parameters to determine the prognosis of CRC patients. CRC samples showed significant upregulation of ADAR1, and high ADAR1 expression was correlated with poor prognosis. Silencing ADAR1 inhibited the proliferation, invasion, and migration of CRC cells and induced ferroptosis by suppressing FAK/AKT activation, and the results of rescue assays were consistent with these mechanisms. Both ADAR1-p110 and ADAR1-p150 were demonstrated to regulate the FAK/AKT pathway, with ADAR1-p110 playing a particularly substantial role. In evaluating the prognosis of CRC patients, combining ADAR1 expression with clinical parameters produced a substantial synergistic effect. The in vivo tumorigenesis of CRC was significantly inhibited by silencing ADAR1. Furthermore, ADAR1 expression was positively correlated with tumor mutational burden (TMB) and microsatellite status (p < 0.05), indicating that ADAR1 plays a complex role in CRC immunotherapy. In conclusion, ADAR1 plays oncogenic roles in CRC both in vitro and in vivo, potentially by inhibiting ferroptosis via downregulation of the FAK/AKT pathway. Thus, ADAR1 serves as a potential prognostic biomarker and a promising target for CRC therapy.

人们对作用于RNA1的腺苷脱氨酶(ADAR1)在结直肠癌(CRC)中的作用知之甚少。本研究探讨了ADAR1及其同工型的作用和潜在分子机制,探索了ADAR1表达与免疫微环境和抗癌药物敏感性之间的相关性,并研究了利用ADAR1表达和临床参数判断CRC患者预后的潜在协同作用。CRC样本显示ADAR1明显上调,ADAR1高表达与预后不良相关。沉默ADAR1可抑制CRC细胞的增殖、侵袭和迁移,并通过抑制FAK/AKT活化诱导铁变态反应。ADAR1-p110和ADAR1-p150都被证明能调节FAK/AKT通路,其中ADAR1-p110的作用尤为重要。在评估 CRC 患者的预后时,将 ADAR1 表达与临床参数相结合会产生很大的协同效应。沉默 ADAR1 能显著抑制 CRC 的体内肿瘤发生。此外,ADAR1的表达与肿瘤突变负荷(TMB)和微卫星状态呈正相关(p
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引用次数: 0
Issue Information ‐ Ed Board 发行信息 - 教育委员会
IF 4.6 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-06 DOI: 10.1002/mc.23579
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引用次数: 0
Case report & review: Bilateral NIFTP harboring concomitant HRAS and KRAS mutation: Report of an unusual case and literature review. 病例报告与综述:同时携带 HRAS 和 KRAS 突变的双侧 NIFTP:罕见病例报告与文献综述。
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-04 DOI: 10.1002/mc.23813
Marianna Rita Brogna, Francesca Collina, Maria Grazia Chiofalo, Debora De Bartolo, Angela Montone, Maria Rosaria Schiano, Michele Del Sesto, Nubia Pizza, Gerardo Ferrara

Diagnosis and treatment of thyroid disease are affected by the wide range of thyroid cancer subtypes and their varying degrees of aggressiveness. To better describe the indolent nature of thyroid neoplasms previously classified as noninvasive follicular variant of papillary thyroid carcinoma (NI-FVPTC), the Endocrine Pathology Society working group has recently coined the term "noninvasive follicular thyroid neoplasm with papillary-like nuclear features" (NIFTP). The purpose of this nomenclature change is to avoid patients the distress of cancer diagnosis and to decrease the overtreatment of thyroid nodules with a RAS-LIKE molecular profile similar to follicular adenoma. Consequently, the reclassification has a significant impact on thyroid nodule clinical care as well as histopathologic and cytopathologic diagnosis. This paper will focus on a unique case of Bilateral NIFTP harboring concomitant HRAS and KRAS mutation; we will also review the background, molecular features, and clinical implications of NIFTP as well as the factors behind the nomenclature update. It also seemed helpful to emphasize the impact of NIFTP on clinical practice to avoid overtreating nodules that could be safely managed with lobectomy alone. Actually, despite the diagnosis is postsurgery, a comprehensive preoperative evaluation may raise a suspicion of NIFTP and suggest a more careful plan for treatment. Here, we present a unique case of bilateral NIFTP after total thyroidectomy; subsequent molecular analysis revealed that the patient's right nodule harbored an isolated p.(Q61K) HRAS mutation, while the left a p.(Q61K) KRAS mutation. To the best of our knowledge, this is the first case report of this nature. The existence of simultaneous mutations highlights the occurrence of intratumoral heterogeneity (ITH) also in the context of FVPTC, which requires comprehensive investigation. The available information shows that NIFTP, identified in accordance with stringent inclusion and exclusion criteria, exhibits a very latent clinical behavior even in the face of conservative lobectomy, lacking of radioactive iodine therapy. However, it cannot be regarded as a benign lesion because there is a small but significant incidence of adverse events, such as lymph nodes and distant metastases. Currently, NIFTP can only be suspected before surgery: several efforts could be explored to identify key molecular, cytological, and ultrasonographic traits that may be helpful in raising the possibility of NIFTP in the preoperative context. Additionally, our discovery of simultaneous mutations within the same lesion strengthens the evidence of ITH even in FVPTC. Although the extent and biological impact of this phenomenon in NIFTP are still debated, a deeper understanding is essential to ensure appropriate clinical management.

甲状腺癌亚型种类繁多,侵袭性程度各异,这影响了甲状腺疾病的诊断和治疗。为了更好地描述以前被归类为甲状腺乳头状癌非侵袭性滤泡变异型(NI-FVPTC)的甲状腺肿瘤的惰性,内分泌病理学协会工作组最近创造了 "具有乳头状核特征的非侵袭性滤泡甲状腺肿瘤"(NIFTP)一词。这一术语变化的目的是避免患者因被诊断为癌症而苦恼,并减少对具有类似滤泡腺瘤的 RAS-LIKE 分子特征的甲状腺结节的过度治疗。因此,重新分类对甲状腺结节的临床治疗以及组织病理学和细胞病理学诊断都有重大影响。本文将重点讨论一例独特的同时携带 HRAS 和 KRAS 突变的双侧 NIFTP;我们还将回顾 NIFTP 的背景、分子特征和临床意义,以及术语更新背后的因素。此外,强调 NIFTP 对临床实践的影响似乎也很有帮助,可避免过度治疗仅通过肺叶切除术就能安全处理的结节。事实上,尽管诊断是在手术后进行的,但全面的术前评估可能会引起对 NIFTP 的怀疑,并建议采取更谨慎的治疗方案。在此,我们介绍了一例独特的甲状腺全切除术后双侧 NIFTP 病例;随后的分子分析显示,患者右侧结节携带孤立的 p.(Q61K) HRAS 突变,而左侧结节携带 p.(Q61K) KRAS 突变。据我们所知,这是首例此类病例报告。同时存在突变突显了 FVPTC 也存在瘤内异质性 (ITH),需要进行全面调查。现有资料表明,根据严格的纳入和排除标准确定的 NIFTP,即使在保守的肺叶切除术和缺乏放射性碘治疗的情况下,也会表现出非常潜伏的临床表现。然而,由于淋巴结和远处转移等不良事件的发生率虽小但却很高,因此不能将其视为良性病变。目前,NIFTP 只能在手术前进行怀疑:可以通过多种努力来确定关键的分子、细胞学和超声特征,这些特征可能有助于在术前提高 NIFTP 的可能性。此外,我们在同一病灶中同时发现了突变,这也加强了 ITH 甚至在 FVPTC 中存在的证据。尽管对这种现象在 NIFTP 中的程度和生物学影响仍有争议,但深入了解这种现象对确保适当的临床管理至关重要。
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引用次数: 0
Diosmetin: A dietary flavone as modulator of signaling pathways in cancer progression. Diosmetin:作为癌症进展信号通路调节剂的一种膳食黄酮。
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-01 Epub Date: 2024-06-18 DOI: 10.1002/mc.23774
Waseem Raza, Abha Meena, Suaib Luqman

Flavonoids, constituting the most extensive category of polyphenols, founds in a variety of plants and comprise over 9000 compounds. Diosmetin, O-methylated flavone (3',5,7-trihydroxy-4'-methoxyflavone) of flavonoid aglycone diosmin have witnessed a significant surge in recent years. Many studies showed that flavonoids induced cytotoxicity in different organ specific cancer types. Thus, current review evaluates the anticancer potential of diosmetin and shed light on its mechanism of action such as cell cycle regulation, apoptosis via both intrinsic and extrinsic pathway, autophagy and tumour progression and metastasis. It also provides comprehensive analysis of different cancer targets and their role in breast, colon, hepatic, gliomas, leukemia, lung, prostate and skin cancer. Combination studies of diosmetin to improve drug sensitivity and reduce toxicity towards normal cells has been also discussed. Besides, in vitro studies, present review also discuss the anticancer potential of diosmetin on xenograft mice model. Different natural sources of diosmetin, limitations, pharmacokinetic analysis and toxicity study also summarized in current review. The emphasis on enhancing solubility and permeability for clinical utility has been thoroughly highlighted with particular attention given to the utilization of nano formulations to overcome existing barriers. At last, in-depth analysis of current challenges and a forward-looking perspective deliberated to address the existing gaps and position it as a promising lead compound for clinical applications in cancer treatment. This discussion is boosted by diosmetin's potential anticancer properties on different cancers, makes valuable candidates in the ongoing quest for effective therapeutic interventions against cancer.

类黄酮是多酚中最广泛的一类,存在于多种植物中,由 9000 多种化合物组成。近年来,黄酮类苷元 diosmin 的 O-甲基化黄酮(3',5,7-三羟基-4'-甲氧基黄酮)出现了显著的增长。许多研究表明,黄酮类化合物可诱导不同器官特定类型癌症的细胞毒性。因此,本综述评估了 diosmetin 的抗癌潜力,并阐明了其作用机制,如细胞周期调节、通过内在和外在途径的细胞凋亡、自噬、肿瘤进展和转移。研究还全面分析了不同癌症靶点及其在乳腺癌、结肠癌、肝癌、胶质瘤、白血病、肺癌、前列腺癌和皮肤癌中的作用。还讨论了为提高对药物的敏感性和减少对正常细胞的毒性而对香叶木素进行的联合研究。除体外研究外,本综述还讨论了香叶木素在异种移植小鼠模型上的抗癌潜力。本综述还总结了不同天然来源的 diosmetin、局限性、药代动力学分析和毒性研究。本综述全面强调了提高溶解度和渗透性以促进临床应用的重要性,并特别关注了利用纳米制剂克服现有障碍的问题。最后,深入分析了当前面临的挑战,并从前瞻性的角度讨论了如何解决现有差距,并将其定位为癌症治疗临床应用中一种前景广阔的先导化合物。这一讨论得到了 diosmetin 对不同癌症的潜在抗癌特性的推动,使其成为目前寻求有效癌症治疗干预措施的宝贵候选化合物。
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引用次数: 0
14-3-3σ/Stratifin and p21 limit AKT-related malignant progression in skin carcinogenesis following MDM2-associated p53 loss. 14-3-3σ/Stratifin和p21可限制MDM2-相关p53缺失后皮肤癌发生过程中与AKT相关的恶性进展。
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-01 Epub Date: 2024-06-13 DOI: 10.1002/mc.23771
Carol M McMenemy, Dajiang Guo, Jean A Quinn, David A Greenhalgh

To study mechanisms driving/inhibiting skin carcinogenesis, stage-specific expression of 14-3-3σ (Stratifin) was analyzed in skin carcinogenesis driven by activated rasHa/fos expression (HK1.ras/fos) and ablation of PTEN-mediated AKT regulation (K14.creP/Δ5PTENflx/flx). Consistent with 14-3-3σ roles in epidermal differentiation, HK1.ras hyperplasia and papillomas displayed elevated 14-3-3σ expression in supra-basal keratinocytes, paralleled by supra-basal p-MDM2166 activation and sporadic p-AKT473 expression. In bi-genic HK1.fos/Δ5PTENflx/flx hyperplasia, basal-layer 14-3-3σ expression appeared, and alongside p53/p21, was associated with keratinocyte differentiation and keratoacanthoma etiology. Tri-genic HK1.ras/fos-Δ5PTENflx/flx hyperplasia/papillomas initially displayed increased basal-layer 14-3-3σ, suggesting attempts to maintain supra-basal p-MDM2166 and protect basal-layer p53. However, HK1.ras/fos-Δ5PTENflx/flx papillomas exhibited increasing basal-layer p-MDM2166 activation that reduced p53, which coincided with malignant conversion. Despite p53 loss, 14-3-3σ expression persisted in well-differentiated squamous cell carcinomas (wdSCCs) and alongside elevated p21, limited malignant progression via inhibiting p-AKT1473 expression; until 14-3-3σ/p21 loss facilitated progression to aggressive SCC exhibiting uniform p-AKT1473. Analysis of TPA-promoted HK1.ras-Δ5PTENflx/flx mouse skin, demonstrated early loss of 14-3-3σ/p53/p21 in hyperplasia and papillomas, with increased p-MDM2166/p-AKT1473 that resulted in rapid malignant conversion and progression to poorly differentiated SCC. In 2D/3D cultures, membranous 14-3-3σ expression observed in normal HaCaT and SP1ras61 papilloma keratinocytes was unexpectedly detected in malignant T52ras61/v-fos SCC cells cultured in monolayers, but not invasive 3D-cells. Collectively, these data suggest 14-3-3σ/Stratifin exerts suppressive roles in papillomatogenesis via MDM2/p53-dependent mechanisms; while persistent p53-independent expression in early wdSCC may involve p21-mediated AKT1 inhibition to limit malignant progression.

为了研究驱动/抑制皮肤癌变的机制,我们分析了 14-3-3σ (Stratifin) 在活化的 rasHa/fos 表达(HK1.ras/fos)和消减 PTEN 介导的 AKT 调节(K14.creP/Δ5PTENflx/flx)驱动的皮肤癌变中的阶段特异性表达。与14-3-3σ在表皮分化中的作用一致,HK1.ras增生和乳头状瘤显示基底层角质细胞中14-3-3σ表达升高,同时基底层p-MDM2166活化和p-AKT473零星表达。在双基因HK1.fos/Δ5PTENflx/flx增生中,基底层出现了14-3-3σ表达,与p53/p21一起与角朊细胞分化和角化棘皮瘤病因有关。三基因HK1.ras/fos-Δ5PTENflx/flx增生/乳头状瘤最初显示基底层14-3-3σ增加,这表明它们试图维持基底层上p-MDM2166并保护基底层p53。然而,HK1.ras/fos-Δ5PTENflx/flx乳头状瘤表现出基底层p-MDM2166激活的增加,从而降低了p53,这与恶性转化相吻合。尽管p53缺失,但14-3-3σ的表达在分化良好的鳞状细胞癌(wdSCC)中持续存在,与p21的升高一起,通过抑制p-AKT1473的表达限制了恶性进展;直到14-3-3σ/p21缺失,才促进了向侵袭性SCC的进展,表现出一致的p-AKT1473。对TPA促进的HK1.ras-Δ5PTENflx/flx小鼠皮肤的分析表明,在增生和乳头状瘤中,14-3-3σ/p53/p21早期丧失,p-MDM2166/p-AKT1473增加,导致快速恶性转化并进展为分化不良的SCC。在二维/三维培养中,正常 HaCaT 细胞和 SP1ras61 乳头状瘤角质形成细胞中观察到的膜状 14-3-3σ 表达意外地在单层培养的恶性 T52ras61/v-fos SCC 细胞中被检测到,但在侵袭性三维细胞中没有检测到。总之,这些数据表明,14-3-3σ/Stratifin 通过 MDM2/p53 依赖性机制在乳头状瘤发生过程中发挥抑制作用;而在早期 wdSCC 中不依赖 p53 的持续表达可能涉及 p21 介导的 AKT1 抑制,从而限制恶性进展。
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引用次数: 0
AURKB targets DHX9 to promote hepatocellular carcinoma progression via PI3K/AKT/mTOR pathway. AURKB 靶向 DHX9,通过 PI3K/AKT/mTOR 通路促进肝细胞癌的进展。
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-01 Epub Date: 2024-06-14 DOI: 10.1002/mc.23775
Guoqing Zhu, Laihui Luo, Yongzhu He, Yongqiang Xiao, Ziwei Cai, Weilai Tong, Wei Deng, Jin Xie, Yanxin Zhong, Zhigao Hu, Renfeng Shan

Aurora kinase B (AURKB) is known to play a carcinogenic role in a variety of cancers, but its underlying mechanism in liver cancer is unknown. This study aimed to investigate the role of AURKB in hepatocellular carcinoma (HCC) and its underlying molecular mechanism. Bioinformatics analysis revealed that AURKB was significantly overexpressed in HCC tissues and cell lines, and its high expression was associated with a poorer prognosis in HCC patients. Furthermore, downregulation of AURKB inhibited HCC cell proliferation, migration, and invasion, induced apoptosis, and caused cell cycle arrest. Moreover, AURKB downregulation also inhibited lung metastasis of HCC. AURKB interacted with DExH-Box helicase 9 (DHX9) and targeted its expression in HCC cells. Rescue experiments further demonstrated that AURKB targeting DHX9 promoted HCC progression through the PI3K/AKT/mTOR pathway. Our results suggest that AURKB is significantly highly expressed in HCC and correlates with patient prognosis. Targeting DHX9 with AURKB promotes HCC progression via the PI3K/AKT/mTOR pathway.

已知极光激酶 B(AURKB)在多种癌症中发挥致癌作用,但其在肝癌中的潜在机制尚不清楚。本研究旨在探讨 AURKB 在肝细胞癌(HCC)中的作用及其分子机制。生物信息学分析表明,AURKB在HCC组织和细胞系中显著高表达,其高表达与HCC患者较差的预后相关。此外,下调 AURKB 可抑制 HCC 细胞的增殖、迁移和侵袭,诱导细胞凋亡,并导致细胞周期停滞。此外,下调AURKB还能抑制HCC的肺转移。AURKB 与 DExH-Box 螺旋酶 9(DHX9)相互作用,并靶向其在 HCC 细胞中的表达。拯救实验进一步证明,靶向DHX9的AURKB通过PI3K/AKT/mTOR通路促进了HCC的进展。我们的研究结果表明,AURKB在HCC中高度表达,并与患者的预后相关。用AURKB靶向DHX9可通过PI3K/AKT/mTOR途径促进HCC的进展。
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引用次数: 0
The cumulative antitumor effects of regorafenib and radiotherapy in hepatocellular carcinoma. 肝细胞癌中瑞戈非尼和放疗的累积抗肿瘤效果。
IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-01 Epub Date: 2024-06-05 DOI: 10.1002/mc.23769
Shuwen Kuang, Jiajun Zhang, Ning Huang, Jing Zhang, Bo Chen, Liming Wang, Mei Liu

Regorafenib is a second-line standard treatment for hepatocellular carcinoma (HCC). However, the efficacy of regorafenib is often limited due to drug resistance, individual differences among patients, and irrational drug use. Radiotherapy (RT) is an important method of localized HCC treatment, and combining RT with other therapies may exert a synergetic antitumor effect. Platelet-derived growth factor receptor-like (PDGFRL) is a tumor suppressor in various solid tumors. However, the function of PDGFRL in HCC is still unknown. In this study, we explored whether regorafenib and RT exert a synergetic effect on the treatment of HCC. The antitumor effect and mechanisms of the combination of regorafenib and RT were verified in a xenograft mouse model in vivo and in HCC cells in vitro. The combination treatment significantly inhibited cell proliferation and promoted apoptosis both in vitro and in vivo. PDGFRL, a potential target of regorafenib, was increased after cumulative treatment in HCC cells, and PDGFRL suppressed HCC cell proliferation and promoted apoptosis by inhibiting STAT3 pathway activation. Furthermore, the cumulative antitumor effect was dependent on the upregulated expression of PDGFRL and inhibition of STAT3 signaling pathway activation in HCC cells. This study increased the understanding of the molecular mechanism underlying the effect of regorafenib plus RT on HCC and provided a theoretical basis for the clinical practice of HCC.

瑞戈非尼是治疗肝细胞癌(HCC)的二线标准疗法。然而,由于耐药性、患者个体差异和不合理用药等原因,瑞戈非尼的疗效往往受到限制。放射治疗(RT)是局部 HCC 治疗的重要方法,RT 与其他疗法联合可发挥协同抗肿瘤作用。血小板衍生生长因子受体样(PDGFRL)是多种实体瘤的肿瘤抑制因子。然而,PDGFRL 在 HCC 中的功能尚不清楚。本研究探讨了瑞戈非尼和 RT 在治疗 HCC 中是否能发挥协同作用。我们在体内异种移植小鼠模型和体外HCC细胞中验证了瑞戈非尼和RT联合治疗的抗肿瘤效果和机制。在体外和体内,联合治疗都能明显抑制细胞增殖并促进细胞凋亡。瑞戈非尼的潜在靶点--PDGFRL在HCC细胞中累积治疗后增加,PDGFRL通过抑制STAT3通路活化抑制HCC细胞增殖并促进细胞凋亡。此外,累积抗肿瘤效应依赖于PDGFRL在HCC细胞中的表达上调和STAT3信号通路活化的抑制。该研究加深了人们对瑞戈非尼加RT治疗HCC的分子机制的认识,为HCC的临床实践提供了理论依据。
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引用次数: 0
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Molecular Carcinogenesis
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