Translational Oncology最新文献

Highlighting function of Wnt signalling in urological cancers: Molecular interactions, therapeutic strategies, and (nano)strategies 强调 Wnt 信号在泌尿系统癌症中的功能：分子相互作用、治疗策略和（纳米）策略

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2024-10-01 DOI: 10.1016/j.tranon.2024.102145

Cancer is a complex, multistep process characterized by abnormal cell growth and metastasis as well as the capacity of the tumor cells in therapy resistance development. The urological system is particularly susceptible to a group of malignancies known as urological cancers, where an accumulation of genetic alterations drives carcinogenesis. In various human cancers, Wnt singalling is dysregulated; following nuclear transfer of β-catenin, it promotes tumor progression and affects genes expression. Elevated levels of Wnt have been documented in urological cancers, where its overexpression enhances growth and metastasis. Additionally, increased Wnt singalling contributes to chemoresistance in urological cancers, leading to reduced sensitivity to chemotherapy agents like cisplatin, doxorubicin, and paclitaxel. Wnt upregulation can change radiotherapy response of urological cancers. The regulation of Wnt involves various molecular pathways, including Akt, miRNAs, lncRNAs, and circRNAs, all of which play roles in carcinogenesis. Targeting and silencing Wnt or its associated pathways can mitigate tumorigenesis in urological cancers. Anti-cancer compounds such as curcumin and thymoquinone have shown efficacy in suppressing tumorigenesis through the downregulation of Wnt singalling. Notably, nanoparticles have proven effective in treating urological cancers, with several studies in prostate cancer (PCa) using nanoparticles to downregulate Wnt and suppress tumor growth. Future research should focus on developing small molecules that inhibit Wnt singalling to further suppress tumorigenesis and advance the treatment of urological cancers. Moreover, Wnt can be used as reliable biomarker for the diagnosis and prognosis of urological cancers.

癌症是一个复杂的多步骤过程，其特点是细胞异常生长和转移，以及肿瘤细胞产生抗药性。泌尿系统特别容易发生一组恶性肿瘤，即泌尿系统癌症，其中基因改变的积累是致癌的驱动力。在各种人类癌症中，Wnt 信号失调；β-catenin 核转移后，促进肿瘤进展并影响基因表达。泌尿系统癌症中的 Wnt 水平升高，其过度表达会促进肿瘤的生长和转移。此外，Wnt 信号的增加也会导致泌尿系统癌症的化疗抗药性，从而降低对顺铂、多柔比星和紫杉醇等化疗药物的敏感性。Wnt 上调可改变泌尿系统癌症的放疗反应。Wnt 的调控涉及多种分子通路，包括 Akt、miRNA、lncRNA 和 circRNA，它们都在致癌过程中发挥作用。靶向和抑制 Wnt 或其相关通路可减轻泌尿系统癌症的肿瘤发生。姜黄素和胸腺醌等抗癌化合物已显示出通过下调 Wnt 信号抑制肿瘤发生的功效。值得注意的是，纳米粒子已被证明能有效治疗泌尿系统癌症，有几项关于前列腺癌（PCa）的研究利用纳米粒子下调 Wnt 并抑制肿瘤生长。未来的研究应侧重于开发抑制 Wnt 单信号的小分子，以进一步抑制肿瘤发生，推动泌尿系统癌症的治疗。此外，Wnt 还可作为可靠的生物标志物，用于诊断和预后泌尿系统癌症。

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引用次数: 0

Transient-resting culture after activation enhances the generation of CD8+ stem cell-like memory T cells from peripheral blood mononuclear cells 活化后的瞬时静止培养可促进外周血单核细胞产生 CD8+ 干细胞样记忆 T 细胞

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2024-10-01 DOI: 10.1016/j.tranon.2024.102138

Adoptive cell therapy (ACT) has revolutionized the treatment of patients with cancer. The success of ACT depends largely on transferred T cell status, particularly their less-differentiated state with stem cell-like properties, which enhances ACT effectiveness. Stem cell-like memory T (T_SCM) cells exhibit continuous self-renewal and multilineage differentiation similar to pluripotent stem cells. T_SCM cells are promising candidates for cancer immunotherapies, whereas maintenance of a more stem-cell-like state before transfer is challenging. Here, we established a highly efficient protocol for generating CD8⁺ T_SCM cells from peripheral blood mononuclear cells (PBMCs). The process involved activating PBMCs using anti-CD3 monoclonal antibody and RetroNectin, followed by a transient-resting culture period (24 h) and subsequent long-term expansion in vitro with interlukien-2. We report that this transient-resting culture after activation preserves CD8⁺ T cells in a stem memory phenotype (CD95⁺ CD45RA⁺ CCR7⁺) compared to the conventional culture method. Further, this approach reduces the expression of T cell immunoglobulin mucin-3, an exhaustion marker, and increases the expression of T cell factor-1, a master regulator of stemness even after long-term culture compared to the conventional culture method. In conclusion, our study presents a simplified and cost-effective method for generating and expanding CD8⁺ T_SCM cells ex vivo. This approach streamlines the optimization of cancer immunotherapy using ACT.

采用细胞疗法（ACT）彻底改变了癌症患者的治疗方法。ACT的成功在很大程度上取决于转移的T细胞状态，特别是它们具有类似干细胞特性的低分化状态，这种状态能提高ACT的效果。干细胞样记忆 T 细胞（TSCM）具有类似多能干细胞的持续自我更新和多系分化能力。TSCM细胞是很有希望的癌症免疫疗法候选细胞，但在转移前维持更像干细胞的状态却很有挑战性。在这里，我们建立了一种高效的方案，从外周血单核细胞（PBMC）中生成 CD8+ TSCM 细胞。这一过程包括使用抗 CD3 单克隆抗体和 RetroNectin 激活 PBMC，然后进行瞬时静止培养（24 小时），随后使用 interlukien-2 在体外进行长期扩增。我们报告说，与传统的培养方法相比，这种活化后的瞬时静止培养能保留干记忆表型（CD95+ CD45RA+ CCR7+）的 CD8+ T 细胞。此外，与传统培养方法相比，这种方法减少了T细胞免疫球蛋白粘蛋白-3（一种衰竭标志物）的表达，增加了T细胞因子-1（一种干性主调节因子）的表达，即使在长期培养后也是如此。总之，我们的研究提出了一种简化且经济高效的体内外生成和扩增 CD8+ TSCM 细胞的方法。这种方法简化了使用 ACT 的癌症免疫疗法的优化过程。

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引用次数: 0

GDF15 and LCN2 for early detection and prognosis of pancreatic cancer 用于胰腺癌早期检测和预后判断的 GDF15 和 LCN2

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2024-09-30 DOI: 10.1016/j.tranon.2024.102129

Background

The prognosis of pancreatic ductal adenocarcinomas (PDAC) remains very poor, emphasizing the critical importance of early detection, where biomarkers offer unique potential. Although growth differentiation factor 15 (GDF15) and Lipocalin 2 (LCN2) have been linked to PDAC, their precise roles as biomarkers are uncertain.

Methods

Circulating levels of GDF15 and LCN2 were examined in human PDAC patients, heathy controls, and individuals with benign pancreatic diseases. Circulating levels of IL-6, CA19-9, and neutrophil-to-lymphocyte ratio (NLR) were measured for comparisons. Correlations between PDAC progression and overall survival were assessed. A mouse PDAC model was employed for comprehensive analyses, complementing the human studies by exploring associations with various metabolic and inflammatory parameters. Sensitivity and specificity of the biomarkers were evaluated.

Findings

Our results demonstrated elevated levels of circulating GDF15 and LCN2 in PDAC patients compared to both healthy controls and individuals with benign pancreatic diseases, with higher GDF15 levels associated with disease progression and increased mortality. In PDAC mice, circulating GDF15 and LCN2 progressively increased, correlating with tumor growth, behavioral manifestations, tissue and molecular pathology, and cachexia development. GDF15 exhibited highly sensitive and specific for PDAC patients compared to CA19-9, IL-6, or NLR, while LCN2 showed even greater sensitivity and specificity in PDAC mice. Combining GDF15 and LCN2, or GDF15 and CA19-9, enhanced sensitivity and specificity.

Interpretation

Our findings indicate that GDF15 holds promise as a biomarker for early detection and prognosis of PDAC, while LCN2 could strengthen diagnostic panels.

背景胰腺导管腺癌（PDAC）的预后仍然很差，强调了早期检测的重要性，而生物标记物在这方面具有独特的潜力。尽管生长分化因子 15 (GDF15) 和脂联素 2 (LCN2) 与 PDAC 有关，但它们作为生物标志物的确切作用尚不确定。为了进行比较，还测量了IL-6、CA19-9和中性粒细胞与淋巴细胞比值（NLR）的循环水平。评估了 PDAC 进展与总生存期之间的相关性。小鼠 PDAC 模型被用来进行综合分析，通过探索与各种代谢和炎症参数的关联来补充人体研究。我们的研究结果表明，与健康对照组和良性胰腺疾病患者相比，PDAC 患者的循环 GDF15 和 LCN2 水平升高，GDF15 水平升高与疾病进展和死亡率增加有关。在 PDAC 小鼠中，循环 GDF15 和 LCN2 逐渐升高，与肿瘤生长、行为表现、组织和分子病理学以及恶病质发展相关。与 CA19-9、IL-6 或 NLR 相比，GDF15 对 PDAC 患者具有高度敏感性和特异性，而 LCN2 在 PDAC 小鼠中显示出更高的敏感性和特异性。我们的研究结果表明，GDF15有望成为PDAC早期检测和预后的生物标记物，而LCN2则可以加强诊断面板。

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引用次数: 0

Bronchial washing fluid sequencing is useful in the diagnosis of lung cancer with necrotic tumor 支气管冲洗液测序有助于诊断伴有坏死肿瘤的肺癌

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2024-09-30 DOI: 10.1016/j.tranon.2024.102134

Background

Early-stage lung cancers detected by low-dose computed tomography (CT) often require confirmation through invasive procedures due to the absence of endobronchial lesions. This study assesses the diagnostic utility of bronchial washing fluid (BW) sequencing, a less invasive alternative, aiming to identify patient characteristics most suited for this approach.

Methods

From June 2017 to March 2018, we conducted a prospective cohort study by enrolling patients with incidental lung lesions suspected of early-stage lung cancer at two independent hospitals, and 114 were diagnosed with lung cancer while 50 were diagnosed with benign lesions. BW sequencing was performed using a targeted gene panel, and the clinical characteristics of patients detected with cancer through sequencing were identified.

Results

Malignant cells were detected in 33 patients (28.9 %) through BW cytology. By applying specificity-focused mutation criteria, BW sequencing classified 42 patients (36.8 %) as having cancer. Among the cancer patients who were BW sequencing positive and BW cytology negative, 15 patients (75.0 %) showed necrosis on CT. The sensitivity of BW sequencing was particularly enhanced in patients with necrotic tumors, reaching 75 %.

Conclusions

BW sequencing presents a viable, non-invasive diagnostic option for early-stage lung cancer, especially valuable in patients with necrotic lesions. By potentially reducing the reliance on more invasive diagnostic procedures, this method could streamline clinical workflows, decrease patient burden, and improve overall diagnostic efficiency.

背景低剂量计算机断层扫描（CT）发现的早期肺癌由于没有支气管内病变，往往需要通过侵入性手术进行确认。本研究评估了支气管冲洗液（BW）测序这一侵入性较小的替代方法的诊断效用，旨在确定最适合这种方法的患者特征。方法从 2017 年 6 月到 2018 年 3 月，我们在两家独立医院开展了一项前瞻性队列研究，招募了偶发肺部病变的疑似早期肺癌患者，其中 114 人被确诊为肺癌，50 人被确诊为良性病变。结果33例患者（28.9%）通过BW细胞学检查发现了恶性细胞。通过采用以特异性为重点的基因突变标准，BW 测序将 42 名患者（36.8%）归类为癌症患者。在 BW 测序阳性、BW 细胞学阴性的癌症患者中，有 15 名患者（75.0%）在 CT 上显示有坏死。结论BW测序为早期肺癌提供了一种可行的非侵入性诊断方法，对有坏死病灶的患者尤其有价值。通过减少对更具侵入性诊断程序的依赖，这种方法可以简化临床工作流程、减轻患者负担并提高整体诊断效率。

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引用次数: 0

Surgery, chemoradiotherapy, or chemoradiation plus immunotherapy: Treatment strategies for nonmetastatic anal squamous cell carcinoma 手术、化放疗或化放疗加免疫疗法：非转移性肛门鳞状细胞癌的治疗策略

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2024-09-30 DOI: 10.1016/j.tranon.2024.102133

The current standard of care for anal squamous cell carcinoma (ASCC) is definitive concurrent chemoradiotherapy (CRT). However, about a third of patients may experience treatment failure. Recently, immunotherapy has emerged as a novel strategy for metastatic ASCC patients. We evaluated the efficacy and safety of surgery, CRT alone, and CRT with immunotherapy (CRT-I) in 100 nonmetastatic ASCC patients, treated from April 2012 through May 2023, by determining survival outcomes and acute adverse events. The median (range) follow-up was 30.7 (7.6 to 134.9) months. The study cohort 3-year overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS), and locoregional recurrence-free survival (LRFS) rates were 80.7 %, 62.2 %, 71.1 %, and 67.6 %, respectively. The Surgery group had significantly lower rates than the CRT and CRT-I groups for 3-year PFS (33.1% vs. 65.2% vs. 92.9 %, P < 0.001), DMFS (46.7% vs. 74.6% vs. 92.9 %, P = 0.002) and LRFS (37.0% vs. 73.3% vs. 92.9 %, P < 0.001), respectively. All patients receiving CRT-I were alive at last follow-up. Of 100 patients, 26 (26.0 %) experienced severe (≥ grade 3) acute toxicity. Of 24 patients receiving CRT-I, 8 (33.3 %) had severe acute toxicity. Using immunohistochemistry, peritumoural stromal infiltration by CD8+ T cells was significantly higher after CRT-I compared to before CRT-I and to after CRT alone. The addition of immunotherapy to CRT may be an effective first-line treatment option with favourable survival outcomes and acceptable toxicity for patients with ASCC. A prospective, randomized trial assessing the efficacy of CRT combined with a PD-1 inhibitor in patients with locally advanced ASCC is in progress.

目前治疗肛门鳞状细胞癌（ASCC）的标准是明确的同步化学放疗（CRT）。然而，约三分之一的患者可能会出现治疗失败。最近，免疫疗法成为治疗转移性肛门鳞状细胞癌患者的一种新策略。我们评估了自2012年4月至2023年5月期间接受治疗的100例非转移性ASCC患者的生存结果和急性不良事件，评估了手术、单纯CRT和CRT联合免疫疗法（CRT-I）的疗效和安全性。随访时间的中位数（范围）为30.7（7.6-134.9）个月。研究队列的3年总生存率（OS）、无进展生存率（PFS）、无远处转移生存率（DMFS）和无局部复发生存率（LRFS）分别为80.7%、62.2%、71.1%和67.6%。手术组的 3 年 PFS（33.1% vs. 65.2% vs. 92.9%，P = 0.001）、DMFS（46.7% vs. 74.6% vs. 92.9%，P = 0.002）和 LRFS（37.0% vs. 73.3% vs. 92.9%，P = 0.001）分别明显低于 CRT 组和 CRT-I 组。所有接受CRT-I治疗的患者在最后一次随访时均存活。在100名患者中，26人（26.0%）出现严重（≥3级）急性毒性。在接受CRT-I治疗的24名患者中，8人（33.3%）出现严重急性毒性。通过免疫组化，CRT-I 后 CD8+ T 细胞的瘤周基质浸润明显高于 CRT-I 前和单纯 CRT 后。对ASCC患者来说，在CRT基础上增加免疫疗法可能是一种有效的一线治疗方案，不仅生存率高，毒性也可接受。一项评估CRT联合PD-1抑制剂对局部晚期ASCC患者疗效的前瞻性随机试验正在进行中。

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引用次数: 0

FERMT1 promotes epithelial-mesenchymal transition of hepatocellular carcinoma by activating EGFR/AKT/β-catenin and EGFR/ERK pathways FERMT1 通过激活表皮生长因子受体/AKT/β-catenin 和表皮生长因子受体/ERK 通路，促进肝细胞癌的上皮-间质转化

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2024-09-30 DOI: 10.1016/j.tranon.2024.102144

Objective

This study aimed to investigate the effects of fermitin family member 1 (FERMT1) on epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma (HCC) via the EGFR/AKT/β-catenin and EGFR/ERK pathways.

Methods

The expression of FERMT1 encoding protein kindlin-1 in HCC tissues was determined by immunohistochemistry, and FERMT1 mRNA expression in HCC tissues and cell lines was analyzed by qRT-PCR. After the FERMT1 expression of SNU182 and SNU387 interfered with siRNA, the cell viability, invasion, migration, and EMT were tested by CCK-8, transwell invasion, scratching, immunofluorescence/WB, respectively. Similarly, the effects of FERMT1 on the viability and metastasis of HCC were investigated in transplanted tumor and lung metastasis mouse models. The protein expressions of EGFR/AKT/β-catenin and EGFR/ERK pathways were analyzed by WB. In addition, the relationship between FERMT1 and EGFR was further determined by immunofluorescence double staining and Co-IP.

Results

FERMT1 was significantly upregulated in HCC, and silencing FERMT1 inhibited the viability, invasion, migration, and EMT of HCC. Silencing FERMT1 also inhibited the activation of EGFR/AKT/β-catenin and EGFR/ERK pathways. In addition, inhibition of EGFR, AKT, or ERK confirmed that EGFR/AKT/β-catenin and EGFR/ERK pathways were involved in the promoting effects of FERMT1 on HCC. Co-IP and immunofluorescence experiments confirmed the targeting relationship between FERMT1 and EGFR.

Conclusion

FERMT1 was highly expressed in HCC and promoted viability, invasion, migration, and EMT of HCC by targeting EGFR to activate the EGFR/AKT/β-catenin and EGFR/ERK pathways. Our study revealed the role of FERMT1 in HCC and suggested that FERMT1 exerts biological effects through activating the EGFR/AKT/β-catenin and EGFR/ERK pathways.

目的本研究旨在探讨费米素家族成员1（FERMT1）通过表皮生长因子受体/AKT/β-酪蛋白和表皮生长因子受体/ERK通路对肝细胞癌（HCC）上皮-间质转化（EMT）的影响。方法采用免疫组化法测定 FERMT1 编码蛋白 kindlin-1 在 HCC 组织中的表达，并采用 qRT-PCR 法分析 FERMT1 mRNA 在 HCC 组织和细胞系中的表达。用siRNA干扰SNU182和SNU387的FERMT1表达后，分别用CCK-8、transwell侵袭、划痕、免疫荧光/WB检测细胞活力、侵袭、迁移和EMT。同样，在移植瘤和肺转移小鼠模型中研究了 FERMT1 对 HCC 的活力和转移的影响。WB 分析了表皮生长因子受体/AKT/β-catenin 和表皮生长因子受体/ERK 通路的蛋白表达。结果FERMT1在HCC中显著上调，沉默FERMT1可抑制HCC的活力、侵袭、迁移和EMT。沉默 FERMT1 还能抑制 EGFR/AKT/β-catenin 和 EGFR/ERK 通路的激活。此外，抑制表皮生长因子受体、AKT或ERK证实了表皮生长因子受体/AKT/β-catenin和表皮生长因子受体/ERK通路参与了FERMT1对HCC的促进作用。结论FERMT1在HCC中高表达，通过靶向表皮生长因子激活表皮生长因子受体/AKT/β-catenin和表皮生长因子受体/ERK通路，促进HCC的活力、侵袭、迁移和EMT。我们的研究揭示了FERMT1在HCC中的作用，并认为FERMT1通过激活表皮生长因子受体/AKT/β-catenin和表皮生长因子受体/ERK通路发挥生物学效应。

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引用次数: 0

Induction of LARP1B under endoplasmic reticulum stress and its regulatory role in proliferation of esophageal squamous cell carcinoma 内质网应激下 LARP1B 的诱导及其在食管鳞状细胞癌增殖中的调控作用

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2024-09-27 DOI: 10.1016/j.tranon.2024.102141

Endoplasmic Reticulum Stress (ER stress) is a series of cellular responses activated in response to misfolded and unfolded protein accumulation and calcium imbalance in the ER lumen. Cumulating evidence emphasized the crucial involvement of ER stress in cell survival, death, and proliferation. However, the precise process remained obscure, especially in esophageal squamous cell carcinoma (ESCC). In the present study, LARP1B was detected to be one of the genes with significant differential expression in the ER stress ESCC cell model by RNA sequencing. ESCC cells exposed to ER stress stimulants (thapsigargin and tunicamycin) showed increased expression levels of LARP1B. ER stress initiated the expression of LARP1B through activation of the ERN1-XBP1 pathway, with XBP1 acting as a transcription factor to boost LARP1B transcription. Up-regulation of LARP1B was detected in ESCC tissues and cell lines. Suppression of LARP1B effectively curtailed the growth of cells and hindered the progression of the cell cycle. By detecting the expression of some genes closely related to proliferation and cell cycle regulation, CCND1 was identified as the main contributor to the cell proliferation induced by LARP1B. As an RNA-binding protein, LARP1B has the capability to attach to CCND1 mRNA, thereby increasing its stability. Inhibiting CCND1 might partially counterbalance the proliferation-promoting impact of LARP1B overexpression on ESCC cells. These findings indicate that, upon ER stress, up-regulation of LARP1B, triggered by ERN1-XBP1 pathway, facilitates proliferation of ESCC cells through enhancing the mRNA stability of CCND1, and LARP1B may be used as a potential therapeutic target of ESCC.

内质网应激（ER应激）是细胞对错误折叠和未折叠蛋白质的积累以及ER腔中的钙失衡做出的一系列反应。越来越多的证据表明，ER 应激对细胞的存活、死亡和增殖至关重要。然而，这一过程的确切过程仍然模糊不清，尤其是在食管鳞状细胞癌（ESCC）中。本研究通过RNA测序发现，LARP1B是ER应激ESCC细胞模型中具有显著差异表达的基因之一。暴露于ER应激刺激物（thapsigargin和tunicamycin）的ESCC细胞显示LARP1B的表达水平升高。ER应激通过激活ERN1-XBP1通路启动了LARP1B的表达，XBP1作为转录因子促进了LARP1B的转录。在 ESCC 组织和细胞系中检测到了 LARP1B 的上调。抑制 LARP1B 能有效抑制细胞的生长，阻碍细胞周期的进展。通过检测一些与细胞增殖和细胞周期调控密切相关的基因的表达，发现CCND1是LARP1B诱导细胞增殖的主要因素。作为一种 RNA 结合蛋白，LARP1B 能够附着在 CCND1 mRNA 上，从而增加其稳定性。抑制 CCND1 可部分抵消 LARP1B 过表达对 ESCC 细胞的增殖促进作用。这些研究结果表明，ER应激时，由ERN1-XBP1通路引发的LARP1B上调可通过增强CCND1的mRNA稳定性来促进ESCC细胞的增殖，LARP1B可作为ESCC的潜在治疗靶点。

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引用次数: 0

The relationship between URG4 and clinicopathologic parameters and its effect on two-year survival in gastric carcinoma 胃癌 URG4 与临床病理参数的关系及其对两年生存率的影响

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2024-09-25 DOI: 10.1016/j.tranon.2024.102122

Aim

Gastric cancer (GC) is the third leading cause of cancer-related deaths worldwide. The present study examined the relationship between Upregulated gene 4 (URG4) expression, an oncogene involved in the development of gastric carcinoma, and clinicopathologic parameters including Human epidermal growth factor receptor 2 (HER2) status. The study aimed to investigate the importance of URG4 as a prognostic factor for 2-year survival in GCs, which are usually in the advanced stage at the time of diagnosis and have a rapid course.

Methods

In 61 patients with GC, URG4 expression results in paraffin blocks were compared with the patients' clinicopathologic, 2-year survival, and HER2 results.

Results

Among the patients, 24 (39 %) had low URG4 scores (scores 0–4) and 37 (61 %) had high URG4 scores (scores 6–9). While the HER2 score was negative in 52 (85 %)patients, it was positive in 9 (15 %). URG4 expression values were significantly correlated with tumor (T) stage and lymphovascular invasion (LVI) (p < 0.005), whereas no significant correlation was determined between other pathological prognostic factors and HER2 status (p > 0.005). During the two-year period, 32 (52 %) patients survived and 29 (48 %) died. The mean duration of survival was 75.20 ± 35.22 weeks. A significant correlation was determined between URG4 values and survival and mortality results (p < 0.05).

Conclusion

We revealed a correlation (p < 0.005) between increased URG4 scores with increased T stage and LVI. We demonstrated an association between increased URG4 expression and survival time and mortality in patients with GC during the first two years of survival (p < 0.005) and URG4 and HER2 yielded similar results as prognostic factors in the survival of the patients URG4 is an essential oncogene in malignancies, especially in gastric GC, requiring further research and development in prognostic and therapeutic areas.

目的胃癌（GC）是全球癌症相关死亡的第三大原因。本研究探讨了上调基因 4（URG4）表达（一种参与胃癌发展的癌基因）与临床病理参数（包括人类表皮生长因子受体 2（HER2）状态）之间的关系。该研究旨在探讨URG4作为胃癌患者2年生存率预后因素的重要性，因为胃癌在诊断时通常处于晚期，病程较快。52例（85%）患者的HER2评分为阴性，9例（15%）为阳性。URG4表达值与肿瘤（T）分期和淋巴管侵犯（LVI）显著相关（p <0.005），而其他病理预后因素与HER2状态之间无显著相关性（p >0.005）。两年期间，32 例（52%）患者存活，29 例（48%）死亡。平均存活时间为（75.20 ± 35.22）周。结论我们发现 URG4 评分增加与 T 期和 LVI 增加之间存在相关性（p< 0.005）。URG4是恶性肿瘤（尤其是胃癌）中一种重要的癌基因，需要在预后和治疗领域进行进一步的研究和开发。

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引用次数: 0

FHL2 activates β-catenin/Wnt signaling by complexing with APC and TRIM63 in lung adenocarcinoma 在肺腺癌中，FHL2通过与APC和TRIM63复合物激活β-catenin/Wnt信号转导

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2024-09-24 DOI: 10.1016/j.tranon.2024.102131

Objectives

Four and a half LIM domain 2 protein (FHL2) was reported to regulate the progression of various cancers and this study aimed to clarify the intrinsic mechanism of FHL2 facilitating the progression of lung adenocarcinoma.

Methods

In this study, bioinformatic analysis and immunohistochemistry staining were used to confirm the FHL2 levels in patients with lung adenocarcinoma. The potential influence of FHL2 on the biological function of lung adenocarcinoma cells was verified in vitro and in vivo. To uncover the potential mechanism contributing to the advance of lung adenocarcinoma, liquid chromatography‒mass spectrometry and immunoprecipitation assays were performed to detect the partners of FHL2.

Results

FHL2 levels were upregulated in lung adenocarcinoma and contributed to a dismal prognosis. Moreover, in vitro and in vivo assays suggested that genetic inhibition of FHL2 undermined the viability, migration and invasion of lung adenocarcinoma cells, while forced expression of FHL2 showed the opposite trend. Mechanistically, liquid chromatography‒mass spectrometry and coimmunoprecipitation assays revealed that FHL2 could function as a scaffold to enhance TRIM63-mediated ubiquitination of APC. The degradation of APC further stabilized β-catenin and activated Wnt signaling pathway.

Conclusion

Collectively, this study uncovered the underlying mechanism by which FHL2 regulates the biological characteristics of tumors and provided a novel target for lung adenocarcinoma treatment.

本研究旨在阐明FHL2促进肺腺癌进展的内在机制。方法本研究采用生物信息学分析和免疫组化染色法确认肺腺癌患者体内的FHL2水平。在体外和体内验证了FHL2对肺腺癌细胞生物功能的潜在影响。为了揭示导致肺腺癌恶化的潜在机制，研究人员采用液相色谱-质谱法和免疫沉淀法检测 FHL2 的合作伙伴。此外，体外和体内试验表明，遗传抑制 FHL2 会削弱肺腺癌细胞的活力、迁移和侵袭，而强迫表达 FHL2 则显示出相反的趋势。从机理上讲，液相色谱-质谱法和共免疫沉淀试验显示，FHL2可作为支架，增强TRIM63介导的APC泛素化。总之，本研究揭示了FHL2调控肿瘤生物学特性的内在机制，为肺腺癌的治疗提供了一个新的靶点。

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引用次数: 0

MicroRNA-376a-3p sensitizes CPT-11-resistant colorectal cancer by enhancing apoptosis and reversing the epithelial-to-mesenchymal transition (EMT) through the IGF1R/PI3K/AKT pathway MicroRNA-376a-3p 通过 IGF1R/PI3K/AKT 途径增强细胞凋亡并逆转上皮细胞向间质转化（EMT），从而使耐受 CPT-11 的结直肠癌变得敏感

IF 5 2区医学 Q2 Medicine

Translational Oncology

Pub Date : 2024-09-23 DOI: 10.1016/j.tranon.2024.102125

Colorectal cancer (CRC) remains the third most prevalent type of cancer worldwide contributing to an estimated 10 % of all cancer cases. CPT-11 is one of the first-line drugs for CRC treatment. Unfortunately, the development of drug resistance significantly exacerbates the adverse impact of CRC. Consequent tumor recurrences and metastasis, years after treatment are the frequently reported incidences. MicroRNAs (miRNA) are short non-coding RNA with the functionality of gene suppression. The insulin-like growth factor type 1 receptor (IGF1R) is a tyrosine kinase receptor frequently upregulated in cancers and is associated with cell survival and drug resistance. MiRNAs are frequently reported to be dysregulated in cancers including CRC. Evidence suggests that dysregulated miRNAs have direct consequences on the biological processes of their target genes. We previously demonstrated that miRNA-376a-3p is upregulated in CPT-11responsive, CRC cells upon treatment with CPT-11. We therefore aimed to investigate the involvement of miRNA-376a-3p in CPT-11 resistance and its probable association with IGF1R-mediated cancer cell survival. Our experimental approach used knockdown and overexpression experiments supplemented with western blot, RT-qPCR, flow cytometry, MTT, and migration assays to achieve our aim. Our data reveals the mechanism through which IGF1R and miRNA-376a-3p perpetrate and attenuate CPT-11 resistance respectively. MiRNA-376a-3p overexpression negatively regulated the IGF1R-induced cell survival, PI3K/AKT pathway, and reversed the epithelial-mesenchymal transition, hence sensitizing resistant cells to CPT-11. Our findings suggests that the miRNA-376a-3p/IGF1R axis holds promise as a potential target to sensitize CRC to CPT-11 in cases of drug resistance.

结肠直肠癌（CRC）仍然是全球第三大高发癌症，估计占所有癌症病例的 10%。CPT-11 是治疗 CRC 的一线药物之一。不幸的是，耐药性的产生大大加剧了 CRC 的不良影响。据报道，治疗多年后肿瘤复发和转移的情况屡见不鲜。微小核糖核酸（miRNA）是一种短的非编码核糖核酸，具有抑制基因的功能。胰岛素样生长因子 1 型受体（IGF1R）是一种在癌症中经常上调的酪氨酸激酶受体，与细胞存活和耐药性有关。据报道，在包括 CRC 在内的癌症中，MiRNAs 经常发生失调。有证据表明，失调的 miRNA 会直接影响其靶基因的生物学过程。我们以前曾证实，在 CPT-11 反应性 CRC 细胞中，miRNA-376a-3p 在 CPT-11 处理后上调。因此，我们旨在研究 miRNA-376a-3p 在 CPT-11 抗性中的参与及其与 IGF1R 介导的癌细胞存活的可能关联。我们的实验方法采用了基因敲除和过表达实验，并辅以 Western blot、RT-qPCR、流式细胞术、MTT 和迁移试验来实现我们的目的。我们的数据揭示了IGF1R和miRNA-376a-3p分别延续和减弱CPT-11耐药性的机制。miRNA-376a-3p的过表达负向调节了IGF1R诱导的细胞存活、PI3K/AKT通路，并逆转了上皮-间质转化，从而使耐药细胞对CPT-11敏感。我们的研究结果表明，miRNA-376a-3p/IGF1R轴有望成为在耐药病例中使CRC对CPT-11敏感的潜在靶点。

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引用次数: 0