Overexpression of CrkL as a novel biomarker for poor prognosis in gastric cancer

Feng, Runhua; Li, Jianfang; Sah, Birendra Kumar; Yuan, Fei; Jin, Xiaolong; Yan, Min; Liu, Bingya; Li, Chen; Zhu, Zhenggang

doi:10.3233/cbm-192435

Cited by 3 publications

(3 citation statements)

References 32 publications

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“…Our above data have clearly demonstrated that CRKL is a direct target gene of GLI2. CRKL is a well‐documented oncogene in several types of cancers, including NSCLC, 15,16 gastric cancer 19 and breast cancer 20 . Thus, it is interesting to test whether GLI2 promotes NSCLC tumorigenesis through CRKL.…”

Section: Resultsmentioning

confidence: 99%

CRKL is a critical target of Hh‐GLI2 pathway in lung adenocarcinoma

Liu

et al. 2021

J Cellular Molecular Medi

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Lung adenocarcinoma (LUAD) is one of the important components of non‐small‐cell lung cancer (NSCLC) and leads to many deaths every year. During the initiation and progression of the LUAD, the Hh‐GLI2 pathway plays critical roles. Several components of this pathway have been shown to be amplified or overexpressed in LUAD, providing this pathway as an attractive target for therapeutics. However, a gap in our understanding of the Hh‐GLI2 pathway is the identity of transcriptional targets of GLI2 that drive LUAD tumorigenesis. Here, we show that the oncogene CRKL is a direct target of GLI2. GLI2 turns on CRKL transcription through binding its second intron. Furthermore, CRKL is an essential mediator for GLI2‐driven proliferation and migration of LUAD cells. Depletion of CRKL blunts Hh‐GLI2 pathway‐mediated cell proliferation and invasion. Lastly, we find that CRKL knockout cells are more sensitive to EGFR‐TKI and chemotherapeutics. Taken together, our work here identifies a specific target for Hh‐related malignancies and provides CRKL as a promising therapeutic target for LUAD.

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Section: Resultsmentioning

confidence: 99%

CRKL is a critical target of Hh‐GLI2 pathway in lung adenocarcinoma

Liu

et al. 2021

J Cellular Molecular Medi

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“…Our recent study has demonstrated that CRKL (22q11) is seldomly but recurrently amplified in laryngeal squamous cell carcinoma 8 . Morover, CRKL is known to be overexpressed in a number of different cancer types, including these of breast 19,20 , gastric 21,22 , endometrial carcinoma 23 and lung 24,25 . Overepression of CRKL is also present in colorectal cancers 26 www.nature.com/scientificreports www.nature.com/scientificreports/ and cervical cancer samples 27 .…”

Section: Discussionmentioning

confidence: 99%

Copy number gains of the putative CRKL oncogene in laryngeal squamous cell carcinoma result in strong nuclear expression of the protein and influence cell proliferation and migration

Kostrzewska-Poczekaj

Bednarek

Jarmuż-Szymczak

et al. 2020

Sci Rep

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Laryngeal squamous cell carcinoma is a major medical problem worldwide. Although our understanding of genetic changes and their consequences in laryngeal cancer has opened new therapeutic pathways over the years, the diagnostic as well as treatment options still need to be improved. in our previous study, we identified CRKL (22q11) as a novel putative oncogene overexpressed and amplified in a subset of LScc tumors and cell lines. Here we analyze to what extent CRKL DnA copy number gains correlate with the higher expression of cRKL protein by performing iHc staining of the respective protein in LScc cell lines (n = 3) and primary tumors (n = 40). Moreover, the importance of CRKL gene in regard to proliferation and motility of LSCC cells was analyzed with the application of RNA interference (siRNA). Beside the physiological cytoplasmic expression, the analysis of LScc tumor samples revealed also nuclear expression of CRKL protein in 10/40 (25%) cases, of which three (7.5%), presented moderate or strong nuclear expression. Similarly, we observed a shift towards aberrantly strong nuclear abundance of the CRKL protein in LSCC cell lines with gene copy number amplifications. Moreover, siRNA mediated silencing of CRKL gene in the cell lines showing its overexpression, significantly reduced proliferation (p < 0.01) as well as cell migration (p < 0.05) rates. Altogether, these results show that the aberrantly strong nuclear localization of cRKL is a seldom but recurrent phenomenon in LScc resulting from the increased DnA copy number and overexpression of the gene. Moreover, functional analyses suggest that proliferation and migration of the tumor cells depend on CRKL expression. Laryngeal squamous cell carcinoma (LSCC) belongs to the highly heterogeneous group of head and neck squamous cell carcinomas (HNSCC). HNSCC is the sixth most common cancer worldwide affecting annually more than 600,000 new patients with mortality rate of approximately 50% 1-3. Hitherto, there are only two targeted therapies approved for HNSCC patients. The first, Cetuximab is based on a monoclonal antibody directed against the epidermal growth factor receptor (EGFR) found recurrently amplified in head and neck cancer cells 4. The

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“…CrkL is a member of the Crk adapter protein family, which is involved in two alternatively spliced isoforms of CRK(Crk I and Crk II), human homolog of avian sarcoma retroviral v‐crk oncogene and Crk‐like protein (CrkL). 7 Recent studies have demonstrated that CrkL acts a pivotal part in cell proliferation and associated with the migration and invasion in range of cancers such as bladder, 8 breast cancers, 9 lung, 10 stomach, 11 and liver. 12 The high expression level of CrkL has been related to advanced‐stage cancers with high‐grade aggressiveness and poor prognosis.…”

Section: Introductionmentioning

confidence: 99%

Silencing of the CrkL gene reverses the doxorubicin resistance of K562/ADR cells through regulating PI3K/Akt/MRP1 signaling

Jiang

Chen

Xie

et al. 2021

Clinical Laboratory Analysis

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Background Doxorubicin is a first‐line chemotherapy agent on human myelogenous leukemia clinical treatment, but the development of chemoresistance has largely limited curative effect. In this study, we aimed to evaluate the biological function and molecular mechanisms of CrkL to Doxorubicin resistance. Methods Quantitative reverse transcription‐PCR (qRT‐PCR) assay was performed to examine the expression of CrkL in K562 and K562/ADR cells. The expression of CrkL was silenced through RNA interference technology. MTT assay and flow cytometry were performed to detect the proliferation inhibition and apoptosis rate after CrkL siRNA transfection. The protein expression changes of PI3K/AKT/MRP1 pathway induced by CrkL siRNA were observed by Western Blot assay. Xenograft tumor model was carried out to observe tumor growth in vivo. Results We observed that silencing of CrkL could effectively increase apoptosis rate induced by doxorubicin and dramatically reversed doxorubicin resistance in K562/ADR cells. Further studies revealed knockdown CrkL expression suppressed PI3K/Akt/MRP1 signaling, which indicated CrkL siRNA reversed doxorubicin effect through regulating PI3K/Akt/MRP1 pathway. In addition, overexpression of MRP1 could evidently reduce apoptosis rate and reversed the inhibitory effects of doxorubicin resistance caused by CrkL siRNA on K562/ADR cells. Finally, in vivo experiments revealed that CrkL silencing acted a tumor‐suppressing role in myelogenous leukemia via regulating PI3K/Akt/MRP1 signaling. Conclusion Together, we indicated that CrkL is up‐regulated in myelogenous leukemia cells and silencing of CrkL could reverse Doxorubicin resistance effectively. These results show a potential novel strategy for intervention chemoresistance in myelogenous leukemia during chemotherapy.

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Overexpression of CrkL as a novel biomarker for poor prognosis in gastric cancer

Cited by 3 publications

References 32 publications

CRKL is a critical target of Hh‐GLI2 pathway in lung adenocarcinoma

CRKL is a critical target of Hh‐GLI2 pathway in lung adenocarcinoma

Copy number gains of the putative CRKL oncogene in laryngeal squamous cell carcinoma result in strong nuclear expression of the protein and influence cell proliferation and migration

Silencing of the CrkL gene reverses the doxorubicin resistance of K562/ADR cells through regulating PI3K/Akt/MRP1 signaling

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