Parallel genome-wide RNAi screens identify lymphocyte-specific protein tyrosine kinase (LCK) as a targetable vulnerability of cell proliferation and chemoresistance in nasopharyngeal carcinoma

Liew, Kitson; Yu, Gibson Qi Sheng; Pua, Lesley Jia Wei; Wong, Li Zhe; Tham, Shiau Ying; Hii, Ling‐Wei; Lim, Wei‐Meng; OuYong, Brian Ming; Looi, Chin-King; Wu, Chun; Chung, Felicia Fei‐Lei; Tan, Lu; Ahmad, Munirah; Khoo, Alan Soo‐Beng; Leong, Chee‐Onn

doi:10.1016/j.canlet.2021.02.006

Cited by 14 publications

(9 citation statements)

References 53 publications

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“…Moreover, the expression of LCK was positively correlated with the expression of PD-1, PD-L1 and CTLA4 ( Figure 10 A–C). However, some studies have shown that the high expression of PD-1/PD-L1 inhibits the sensitivity of HCC patients to ICIs [ 33 ], and some studies have shown that the high expression of PD-1/PD-L1 can be used as a benchmark for evaluating HCC immunotherapy [ 34 ]. Therefore, to further prove the influence of LCK expression on the response to immunotherapy, we used the MCP-counter algorithm to generate an immune score heatmap based on the differences in LCK expression in the TCGA data ( Figure 10 D,E); the results showed that the immune score of the group with high LCK expression was significantly higher than that of the group with low LCK expression, p < 0.05 (the higher the immune score, the higher the sensitivity of tumour patients to drugs).…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, ICIs can indirectly activate TLSs by blocking the PD-1/PD-L1 pathway and thereby activate the expression of immune cells, thus, enhancing the anti-tumour effect [ 58 ]. For example, nivolumab and pembrolizumab treat advanced liver cancer by reducing the expression of PD-1 and thereby decreasing T cell depletion [ 33 ]. In addition, high expression of PD-L1 can increase the level of AFP in the blood of HCC patients, thus, promoting tumour progression [ 59 ].…”

Section: Discussionmentioning

confidence: 99%

“…Lymphocyte-specific protein tyrosine kinase (LCK) is a member of the Src family of protein tyrosine kinases [ 30 ]. LCK is a key signalling molecule that functions in T cell maturation, mediates T cell metastasis and enhances the anti-tumour effects of T cells in response to stimulation by chemokines [ 31 , 32 , 33 ]. In patients with nasopharyngeal carcinoma, LCK promotes tumour proliferation and increases drug resistance [ 31 ].…”

Section: Introductionmentioning

confidence: 99%

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Effect of Tertiary Lymphoid Structures on Prognosis of Patients with Hepatocellular Carcinoma and Preliminary Exploration of Its Formation Mechanism

Nie

Jia

et al. 2022

Cancers

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Background: Tertiary lymphoid structures (TLSs) are formed by the aggregation of tumour-infiltrating lymphocytes (TILs), which is driven by chemokines or cytokines in the tumour microenvironment. Studies have shown that TLSs are associated with good prognosis in patients with various solid tumours and can improve patient responses to immunotherapy. However, the role of TLSs in hepatocellular carcinoma (HCC) remains controversial, and the underlying molecular mechanism is unclear. Methods: According to haematoxylin-eosin (HE) staining results, HCC patients in Xijing Hospital data and TCGA data were divided into TLS+ and TLS- groups, and Kaplan–Meier (KM) analysis was performed to assess overall survival (OS) and recurrence-free survival (RFS). Immunofluorescence (IF) and immunohistochemistry (IHC) were used to identify TILs in the TLS+ group. Lymphocyte-specific protein tyrosine kinase (LCK), a molecule involved in TLS formation, was explored in LinkedOmics. TILs were divided into two groups by drawing receiver operating characteristic (ROC) curves to calculate cut-off values. Spearman correlation analysis was used to calculate the correlation between LCK and TILs, and the molecular pathways by which LCK regulates immunotherapy were clarified through enrichment analysis. The half-maximal inhibitory concentration (IC50) distribution of sorafenib was observed in groups that varied in LCK expression. Results: According to the HE results, 61 cases in the Xijing Hospital cohort and 195 cases in the TCGA cohort had TLSs, while 89 cases and 136 cases did not. The KM results showed that TLSs had no effect on the OS of HCC patients but significantly affected RFS. The IF/IHC results showed that higher TIL numbers in TLSs were correlated with better prognosis in HCC patients. Spearman correlation analysis showed that LCK expression was positively correlated with TIL numbers. Enrichment analysis showed that upregulation of LCK expression mainly regulated the cytokine signalling pathway, the chemokine signalling pathway and T-cell activation. The IC50 scores of sorafenib in HCC patients with high LCK expression were lower, and the sensitivity was higher. Conclusion: TLSs mainly affected the early RFS of HCC patients but had no effect on OS. The high expression of the TLS formation-related gene LCK can increase the sensitivity of HCC patients to ICIs.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effect of Tertiary Lymphoid Structures on Prognosis of Patients with Hepatocellular Carcinoma and Preliminary Exploration of Its Formation Mechanism

Nie

Jia

et al. 2022

Cancers

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“…24 It belonged to the Src kinase family and had a hand in signal transduction downstream of many cell surface receptors, 24 the phosphorylation of it on T cell receptors was a key step in the establishment and connection of signals in the process of T cell activation. 25 Besides, LCK has been covered that it express highly in a great majority of tumors, such as breast cancer, 26,27 nasopharyngeal carcinoma 28 and glioma. 29 In addition to leukemia, some solid tumors have been treated with pan-Src family kinase inhibitors, such as dasatinib and saracatinib, both of which are effective in inhibiting tumor growth.…”

Section: Discussionmentioning

confidence: 99%

Identification of Biomarkers Related to Regulatory T Cell Infiltration in Oral Squamous Cell Carcinoma Based on Integrated Bioinformatics Analysis

Wang¹,

Chen²,

Yang³

et al. 2022

IJGM

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Background: Oral squamous cell carcinoma (OSCC) is one of the most prevalent malignancies worldwide. More recently, the administration of immune checkpoint inhibitors has opened up more possibilities for cancer treatment. Methods: We utilized a weighted gene co-expression network and the single sample gene set enrichment analysis (ssGSEA) algorithm in the TCGA database and identified a module highly correlated with regulatory T cell (Treg) abundance in OSCC. Subsequently, we verified the results by tissue microarrays and utilized immunohistochemical staining (IHC) to test the relationship between the expression level and clinicopathological staging. CCK-8, transwell, and wound healing assays were utilized to detect the functions of OSCC cells. Results: LCK, IL10RA, and TNFRSF1B were selected as biomarkers related to regulatory T cell infiltration. IHC staining showed significantly increased expression of LCK, IL10RA or TNFRSF1B in OSCC patients, and the expression levels were associated with tumor stage, lymph node metastasis, pathological stage, clinical status and the overall survival. In vitro experiments showed that LCK, IL10RA or TNFRSF1B knockdown efficiently impaired the proliferative, migrative, and invasive capacity in OSCC cell lines. Conclusion:We performed a series of bioinformatics analyses in OSCC and identified three oncogenic indicators: LCK, IL10RA, TNFRSF1B. These findings uncovered the potential prognostic values of hub genes, thus laying foundations for in-depth research in OSCC.

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“…The most common pathological type of NPC is non-keratinizing carcinoma with a high degree of malignancy, metastasis, and proliferative ability [ 5 ]. The onset of NPC is hard to detect, so early diagnosis is rare, and NPC has often already progressed into middle or late stage by the time it is detected [ 6 ]. While radiotherapy and chemotherapy can effectively control the growth of local tumors, local recurrence and distant metastasis contribute to the low survival rate of patients with NPC [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

Splicing factor derived circular RNA circCAMSAP1 accelerates nasopharyngeal carcinoma tumorigenesis via a SERPINH1/c-Myc positive feedback loop

Wang

Yan

et al. 2022

Mol Cancer

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Background Circular RNAs play an important role in tumor genesis and progression, but they have not been sufficiently studied in patients with nasopharyngeal carcinoma (NPC). Methods The circular RNA, circCAMSAP1, was screened in NPC cells by RNA sequencing analysis. The expression of circCAMSAP1 in NPC tissues was examined by real-time quantitative polymerase chain reaction (RT-qPCR) and in situ hybridization. Wound-healing, transwell, MTT and flow cytometry assays, and nude mouse tumor models were used to explore the effect of circCAMSAP1 on proliferation and metastasis of NPC in vitro or in vivo. The downstream proteins regulated by circCAMSAP1 were screened using mass spectrometry. The interaction between circCAMSAP1 and the SERPINH1 mRNA was identified using the circular RNA immunoprecipitation method and the luciferase reporter assay. The interaction between SERPINH1 and transcription factor c-Myc was verified through Co-immunoprecipitation (Co-IP) and immunofluorescence. The effect of c-Myc on the generation of circCAMSAP1 was examined through RT-qPCR and chromatin immunoprecipitation. Finally, the splicing factors that promote the production of circCAMSAP1 were explored by RT-qPCR and RNA immunoprecipitation (RIP). Results We found that circCAMSAP1 was highly expressed in NPC tissues and promoted NPC proliferation and metastasis. Additionally, circCAMSAP1 promoted SERPINH1 expression through improved SERPINH1 mRNA stability by binding to the 3′-untranslated region (3’UTR) of SERPINH1. Highly expressed SERPINH1 reduced the ubiquitination-degradation rate of c-Myc, causing increased tumorigenesis. Meanwhile, c-Myc, cooperating with splicing factor 10 (SRSF10), could also promote CAMSAP1 pre-mRNA transcription and back-splicing, forming a positive feedback of circCAMSAP1 production, resulting in the proliferation and metastasis of NPC. Conclusions Our findings revealed that circCAMSAP1 promotes NPC proliferation and metastasis by binding to the 3’UTR of SERPINH1, suggesting that the positive feedback of circCAMSAP1-SERPINH1-c-Myc may serve as a prognostic biomarker or therapeutic target in patients with NPC.

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Parallel genome-wide RNAi screens identify lymphocyte-specific protein tyrosine kinase (LCK) as a targetable vulnerability of cell proliferation and chemoresistance in nasopharyngeal carcinoma

Cited by 14 publications

References 53 publications

Effect of Tertiary Lymphoid Structures on Prognosis of Patients with Hepatocellular Carcinoma and Preliminary Exploration of Its Formation Mechanism

Effect of Tertiary Lymphoid Structures on Prognosis of Patients with Hepatocellular Carcinoma and Preliminary Exploration of Its Formation Mechanism

Identification of Biomarkers Related to Regulatory T Cell Infiltration in Oral Squamous Cell Carcinoma Based on Integrated Bioinformatics Analysis

Splicing factor derived circular RNA circCAMSAP1 accelerates nasopharyngeal carcinoma tumorigenesis via a SERPINH1/c-Myc positive feedback loop

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