Pub Date : 2024-10-01DOI: 10.1016/j.tranon.2024.102138
Guangyu Chen , Long Yuan , Yong Zhang , Tiepeng Li , Hongqin You , Lu Han , Peng Qin , Yao Wang , Xue Liu , Jindong Guo , Mengyu Zhang , Kuang Zhang , Linlin Li , Peng Yuan , Benling Xu , Quanli Gao
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 (TSCM) cells exhibit continuous self-renewal and multilineage differentiation similar to pluripotent stem cells. TSCM 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+ TSCM 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+ TSCM cells ex vivo. This approach streamlines the optimization of cancer immunotherapy using ACT.
{"title":"Transient-resting culture after activation enhances the generation of CD8+ stem cell-like memory T cells from peripheral blood mononuclear cells","authors":"Guangyu Chen , Long Yuan , Yong Zhang , Tiepeng Li , Hongqin You , Lu Han , Peng Qin , Yao Wang , Xue Liu , Jindong Guo , Mengyu Zhang , Kuang Zhang , Linlin Li , Peng Yuan , Benling Xu , Quanli Gao","doi":"10.1016/j.tranon.2024.102138","DOIUrl":"10.1016/j.tranon.2024.102138","url":null,"abstract":"<div><div>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<sub>SCM</sub>) cells exhibit continuous self-renewal and multilineage differentiation similar to pluripotent stem cells. T<sub>SCM</sub> 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<sup>+</sup> T<sub>SCM</sub> 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 <em>in vitro</em> with interlukien-2. We report that this transient-resting culture after activation preserves CD8<sup>+</sup> T cells in a stem memory phenotype (CD95<sup>+</sup> CD45RA<sup>+</sup> CCR7<sup>+</sup>) 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<sup>+</sup> T<sub>SCM</sub> cells <em>ex vivo</em>. This approach streamlines the optimization of cancer immunotherapy using ACT.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"50 ","pages":"Article 102138"},"PeriodicalIF":5.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142359650","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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.
{"title":"Highlighting function of Wnt signalling in urological cancers: Molecular interactions, therapeutic strategies, and (nano)strategies","authors":"Mehrdad Hashemi , Mahdi Rezaei , Hadi Rezaeiaghdam , Behdokht Jamali , Zeinab Khazaei Koohpar , Mahsa Tanha , Anahita Bizhanpour , Saba Asadi , Ali Moghadas Jafari , Elaheh Mohandesi Khosroshahi , Maedeh Eslami , Shokooh Salimimoghadam , Noushin Nabavi , Mohsen Rashidi , Eisa Fattah , Afshin Taheriazam , Maliheh Entezari","doi":"10.1016/j.tranon.2024.102145","DOIUrl":"10.1016/j.tranon.2024.102145","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"50 ","pages":"Article 102145"},"PeriodicalIF":5.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142359655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-30DOI: 10.1016/j.tranon.2024.102129
Xinxia Zhu , Brennan Olson , Dove Keith , Mason A Norgard , Peter R Levasseur , Parham Diba , Sara Protzek , Ju Li , Xiaolin Li , Tetiana Korzun , Ariana L Sattler , Abigail C Buenafe , Aaron J Grossberg , Daniel L Marks
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.
{"title":"GDF15 and LCN2 for early detection and prognosis of pancreatic cancer","authors":"Xinxia Zhu , Brennan Olson , Dove Keith , Mason A Norgard , Peter R Levasseur , Parham Diba , Sara Protzek , Ju Li , Xiaolin Li , Tetiana Korzun , Ariana L Sattler , Abigail C Buenafe , Aaron J Grossberg , Daniel L Marks","doi":"10.1016/j.tranon.2024.102129","DOIUrl":"10.1016/j.tranon.2024.102129","url":null,"abstract":"<div><h3>Background</h3><div>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.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Findings</h3><div>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.</div></div><div><h3>Interpretation</h3><div>Our findings indicate that GDF15 holds promise as a biomarker for early detection and prognosis of PDAC, while LCN2 could strengthen diagnostic panels.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"50 ","pages":"Article 102129"},"PeriodicalIF":5.0,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142359654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-30DOI: 10.1016/j.tranon.2024.102134
Jun Hyeok Lim , Hyun-Tae Shin , Sunmin Park , Woo Kyung Ryu , Lucia Kim , Kyung-Hee Lee , Sung Min Ko , Seung Jae Lee , Jung Soo Kim , Jeong-Seon Ryu
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.
{"title":"Bronchial washing fluid sequencing is useful in the diagnosis of lung cancer with necrotic tumor","authors":"Jun Hyeok Lim , Hyun-Tae Shin , Sunmin Park , Woo Kyung Ryu , Lucia Kim , Kyung-Hee Lee , Sung Min Ko , Seung Jae Lee , Jung Soo Kim , Jeong-Seon Ryu","doi":"10.1016/j.tranon.2024.102134","DOIUrl":"10.1016/j.tranon.2024.102134","url":null,"abstract":"<div><h3>Background</h3><div>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.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>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 %.</div></div><div><h3>Conclusions</h3><div>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.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"50 ","pages":"Article 102134"},"PeriodicalIF":5.0,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142359656","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-30DOI: 10.1016/j.tranon.2024.102133
Fang He , Mo Chen , Qi-jun Yao , Zhi-min Liu , Yandong Zhao , Fengyun Pei , Jian Zheng , Yuan-hong Gao , Jun Huang
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。
{"title":"Surgery, chemoradiotherapy, or chemoradiation plus immunotherapy: Treatment strategies for nonmetastatic anal squamous cell carcinoma","authors":"Fang He , Mo Chen , Qi-jun Yao , Zhi-min Liu , Yandong Zhao , Fengyun Pei , Jian Zheng , Yuan-hong Gao , Jun Huang","doi":"10.1016/j.tranon.2024.102133","DOIUrl":"10.1016/j.tranon.2024.102133","url":null,"abstract":"<div><div>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 %, <em>P</em> < 0.001), DMFS (46.7% vs. 74.6% vs. 92.9 %, <em>P</em> = 0.002) and LRFS (37.0% vs. 73.3% vs. 92.9 %, <em>P</em> < 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+ <em>T</em> 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.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"50 ","pages":"Article 102133"},"PeriodicalIF":5.0,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142359652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-30DOI: 10.1016/j.tranon.2024.102144
Wubin Guo , Mengnan Liu , Wei Luo , Jing Peng , Fei Liu , Xin Ma , Li Wang , Sijin Yang
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.
{"title":"FERMT1 promotes epithelial-mesenchymal transition of hepatocellular carcinoma by activating EGFR/AKT/β-catenin and EGFR/ERK pathways","authors":"Wubin Guo , Mengnan Liu , Wei Luo , Jing Peng , Fei Liu , Xin Ma , Li Wang , Sijin Yang","doi":"10.1016/j.tranon.2024.102144","DOIUrl":"10.1016/j.tranon.2024.102144","url":null,"abstract":"<div><h3>Objective</h3><div>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.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>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.</div></div><div><h3>Conclusion</h3><div>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.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"50 ","pages":"Article 102144"},"PeriodicalIF":5.0,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142359653","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-27DOI: 10.1016/j.tranon.2024.102141
Xia Yang , Juntao Lu , Fangyu Su , Junhong Wu , Xinhao Wang , Zhaokun Hu , Zhaoyang Yan , Huanchen Xu , Xiaobin Shang , Wei Guo
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.
{"title":"Induction of LARP1B under endoplasmic reticulum stress and its regulatory role in proliferation of esophageal squamous cell carcinoma","authors":"Xia Yang , Juntao Lu , Fangyu Su , Junhong Wu , Xinhao Wang , Zhaokun Hu , Zhaoyang Yan , Huanchen Xu , Xiaobin Shang , Wei Guo","doi":"10.1016/j.tranon.2024.102141","DOIUrl":"10.1016/j.tranon.2024.102141","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"50 ","pages":"Article 102141"},"PeriodicalIF":5.0,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142327814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-25DOI: 10.1016/j.tranon.2024.102122
Ethem Ömeroğlu
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.
{"title":"The relationship between URG4 and clinicopathologic parameters and its effect on two-year survival in gastric carcinoma","authors":"Ethem Ömeroğlu","doi":"10.1016/j.tranon.2024.102122","DOIUrl":"10.1016/j.tranon.2024.102122","url":null,"abstract":"<div><h3>Aim</h3><div>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.</div></div><div><h3>Methods</h3><div>In 61 patients with GC, URG4 expression results in paraffin blocks were compared with the patients' clinicopathologic, 2-year survival, and HER2 results.</div></div><div><h3>Results</h3><div>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) (<em>p</em> < 0.005), whereas no significant correlation was determined between other pathological prognostic factors and HER2 status (<em>p</em> > 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 (<em>p</em> < 0.05).</div></div><div><h3>Conclusion</h3><div>We revealed a correlation (<em>p</em> < 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 (<em>p</em> < 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.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"50 ","pages":"Article 102122"},"PeriodicalIF":5.0,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142320243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-24DOI: 10.1016/j.tranon.2024.102131
Jian Gao , Yong-Qiang Ao , Jie Deng , Miao Lin , Shuai Wang , Jia-Hao Jiang , Jian-Yong Ding
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.
{"title":"FHL2 activates β-catenin/Wnt signaling by complexing with APC and TRIM63 in lung adenocarcinoma","authors":"Jian Gao , Yong-Qiang Ao , Jie Deng , Miao Lin , Shuai Wang , Jia-Hao Jiang , Jian-Yong Ding","doi":"10.1016/j.tranon.2024.102131","DOIUrl":"10.1016/j.tranon.2024.102131","url":null,"abstract":"<div><h3>Objectives</h3><div>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.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>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.</div></div><div><h3>Conclusion</h3><div>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.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"50 ","pages":"Article 102131"},"PeriodicalIF":5.0,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1936523324002584/pdfft?md5=76a9818eb0ecda2b1f964925fb7005c9&pid=1-s2.0-S1936523324002584-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142315103","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-23DOI: 10.1016/j.tranon.2024.102125
Chikondi Jassi , Wei-Wen Kuo , Yu-Chun Chang , Tso-Fu Wang , Tsung-Jung Ho , Dennis Jine-Yuan Hsieh , Chia-Hua Kuo , Ming-Cheng Chen , Chi-Cheng Li , Chih-Yang Huang
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.
{"title":"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","authors":"Chikondi Jassi , Wei-Wen Kuo , Yu-Chun Chang , Tso-Fu Wang , Tsung-Jung Ho , Dennis Jine-Yuan Hsieh , Chia-Hua Kuo , Ming-Cheng Chen , Chi-Cheng Li , Chih-Yang Huang","doi":"10.1016/j.tranon.2024.102125","DOIUrl":"10.1016/j.tranon.2024.102125","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"50 ","pages":"Article 102125"},"PeriodicalIF":5.0,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1936523324002523/pdfft?md5=cc1f8ffe40666f9a6ab8833d9fad58c2&pid=1-s2.0-S1936523324002523-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142311145","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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