squamous cell lung carcinoma
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eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
E Josue Ruiz ◽  
Adan Pinto-Fernandez ◽  
Andrew P Turnbull ◽  
Linxiang Lan ◽  
Thomas M Charlton ◽  
...  

Lung squamous cell carcinoma (LSCC) is a considerable global health burden, with an incidence of over 600,000 cases per year. Treatment options are limited, and patient 5-year survival rate is less than 5%. The ubiquitin specific protease 28 (USP28) has been implicated in tumorigenesis through its stabilization of the oncoproteins c-MYC, c-JUN and Dp63. Here, we show that genetic inactivation of Usp28 induced regression of established murine LSCC lung tumours. We developed a small molecule that inhibits USP28 activity in the low nanomole range. While displaying cross-reactivity against the closest homologue USP25, this inhibitor showed a high degree of selectivity over other deubiquitinases. USP28 inhibitor treatment resulted in a dramatic decrease in c-MYC, c-JUN and Dp63 proteins levels and consequently induced substantial regression of autochthonous murine LSCC tumors and human LSCC xenografts, thereby phenocopying the effect observed by genetic deletion. Thus, USP28 may represent a promising therapeutic target for the treatment of squamous cell lung carcinoma.


2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Qingqing Wu ◽  
Xiaoyang Luo ◽  
Mikkel G. Terp ◽  
Qingrun Li ◽  
Yuan Li ◽  
...  

Abstract Background Early recurrence is a major obstacle to prolonged postoperative survival in squamous cell lung carcinoma (SqCLC). The molecular mechanisms underlying early SqCLC recurrence remain unclear, and effective prognostic biomarkers for predicting early recurrence are needed. Methods We analyzed primary tumor samples of 20 SqCLC patients using quantitative proteomics to identify differentially-expressed proteins in patients who experienced early versus late disease recurrence. The expression and prognostic significance of DDX56 was evaluated using a SqCLC tumor tissue microarray and further verified using different online databases. We performed in vitro and in vivo experiments to obtain detailed molecular insight into the functional role of DDX56 in SqCLC. Results We found that DDX56 exhibited increased expression in tumors of patients who experienced early versus late disease recurrence. Increased DDX56 expression in SqCLC tumors was subsequently confirmed as an independent prognostic factor of poor recurrence-free survival in independent SqCLC cohorts. Functionally, DDX56 promotes SqCLC cell growth and migration in vitro, and xenograft tumor progression in vivo. Mechanistically, DDX56 post-transcriptionally promotes expression of multiple Wnt signaling pathway-related genes, including CTNNB1, WNT2B, and represses a subset of miRNAs, including miR-378a-3p, a known suppressor of Wnt signaling. Detailed analysis revealed that DDX56 facilitated degradation of primary miR-378a, leading to down-regulation of mature miR-378a-3p and thus derepression of the target gene WNT2B. Conclusion We identified DDX56 as a novel independent prognostic biomarker that exerts its oncogenic effects through miRNA-mediated post-transcriptional regulation of Wnt signaling genes to promote early SqCLC recurrence. DDX56 may assist in identifying SqCLC patients at increased risk of early recurrence and who could benefit from Wnt signaling-targeted therapies.


2021 ◽  
Author(s):  
Hikaru Aoki ◽  
Keigo Uchimura ◽  
Tatsuya Imabayashi ◽  
Yuji Matsumoto ◽  
Masahiro Higashiyama ◽  
...  

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jii Bum Lee ◽  
Min Hee Hong ◽  
Seong Yong Park ◽  
Sehyun Chae ◽  
Daehee Hwang ◽  
...  

2021 ◽  
Vol 11 ◽  
Author(s):  
Liping Hao ◽  
Ying Hu ◽  
Jianjun Hu ◽  
Yang Liu ◽  
Beibei Mao ◽  
...  

Clinical trials indicated that PD-1/PD-L1 inhibitors significantly improve the survival rate of patients with advanced non-small cell lung cancer (NSCLC) and induce immune-related adverse events (irAEs). Thus, the molecular and immune characteristics during PD-1/PD-L1 inhibitor therapy are worth investigating further. We report the case of a 62-year-old male patient diagnosed with stage IIIA squamous cell lung carcinoma (SQCC) who responded to neoadjuvant and adjuvant nivolumab combined chemotherapy but died from anastomosis leakage or/and irAEs. In the pretreatment tumor biopsy, PD-L1 expression was negative and a few T cells, NK cells, and macrophages had infiltrated the tumor. Wild-type EGFR/STK11, mutant TP53, microsatellite stability, and low tumor mutational burden were also found at baseline. After neoadjuvant immunochemotherapy, the tumor was significantly reduced, PD-L1 expression levels were increased by 50%, and more CD8+ and CD8+ PD-1+ T cells had infiltrated the resected tumor tissue. Immune-related lung injury occurred during adjuvant immunochemotherapy, and serum levels of C-reactive protein, IL-13, IL-4, eotaxin, VEGF-A, IL-8, and IFN-gamma were increased. This case demonstrates a squamous cell lung carcinoma patient who responded to neoadjuvant immunochemotherapy that reshaped the tumor immune environment from “cold” to “hot.” Unfortunately, the patient eventually died from anastomosis leakage or/and irAEs during adjuvant immunochemotherapy.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jii Bum Lee ◽  
Min Hee Hong ◽  
Seong Yong Park ◽  
Sehyun Chae ◽  
Daehee Hwang ◽  
...  

AbstractTargeting T-Cell Immunoreceptor with Ig and ITIM domain-poliovirus receptor (PVR) pathway is a potential therapeutic strategy in lung cancer. We analyzed the expression of PVR and programmed death ligand-1 (PD-L1) in surgically resected squamous cell lung carcinoma (SQCC) and determined its prognostic significance. We collected archival surgical specimens and data of 259 patients with SQCC at Yonsei Cancer Center (1998–2020). Analysis of variance was used to analyze the correlations between PVR and PD-L1 expression and patient characteristics. Kaplan–Meier curves were used to estimate recurrence-free survival (RFS) and overall survival (OS). Most patients were male (93%); the majority were diagnosed with stage 1 (47%), followed by stage 2 (29%) and stage 3 (21%). Overexpression of PVR resulted in a significantly shorter median RFS and OS (P = 0.01). PD-L1 expression was not significant in terms of prognosis. Patients were subdivided into four groups based on low and high PVR and PD-L1 expression. Those expressing high levels of PVR and PD-L1 had the shortest RFS (P = 0.03). PVR overexpression is associated with a poor prognosis in surgically resected SQCC. Inhibition of PVR as well as PD-L1 may help overcome the lack of response to immune checkpoint monotherapy.


2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yohei Maki ◽  
Yoshifumi Kimizuka ◽  
Koji Murakami ◽  
Kimiya Sato ◽  
Hisashi Sasaki ◽  
...  

Abstract Background Zosteriform skin metastasis (ZSM) is rare, and its etiology is not well understood. ZSM is possibly derived from the retrograde movement of cancer cells through the lymphatic vessels during disease development. However, it has been difficult to demonstrate it, as no specific findings have been observed. Case presentation A 68-year-old man presented to our department with neck lymphadenopathy. After detailed examinations, squamous cell lung carcinoma (cT2aN3M1c) was diagnosed. Although cisplatin combined with gemcitabine was administered, his cancerous lymphangiopathy was exacerbated, and ZSM was observed on his right chest. Pembrolizumab was initiated as a second-line chemotherapy; however, the patient died 7 months after the initial presentation. In this case, fluorodeoxyglucose-positron emission tomography indicated the presence of skin metastasis and cancerous lymphangiopathy. Similarly, after performing an autopsy, tumor-cell filled lymph ducts were observed in the right subclavian and the cutaneous lymphatic vessel from the right hilar lymph nodes. Conclusions To the best of our knowledge, this is the first study to demonstrate that the localization of ZSM in the cutaneous lymphatics was caused by the retrograde movement of cancer cells through the lymphatic vessels, using radiographical and pathological analysis. In addition, fluorodeoxyglucose-positron emission tomography may help predict skin metastasis induced by cancerous lymphangiopathy.


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