Serine-arginine protein kinase 1 is associated with hepatocellular carcinoma progression and poor patient survival

Zhang, Jing; Jiang, Hua; Xia, Wenfei; Jiang, Yi‐Zhou; Tan, Xiaohong; Liu, Peiying; Jia, Hongyun; Yang, Xiao; Shen, Gang

doi:10.1007/s13277-015-3771-x

Cited by 9 publications

(12 citation statements)

References 28 publications

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“…4a). Previous studies have demonstrated that SRPK1 is highly expressed in HCC cells and tissues, and associates with poor prognosis and aggressive phenotype of HCC [25, 26]. To confirm this hypothesis, we performed qRT-PCR and Western blot analysis and found that ectopic expression of miR-1296 dramatically decreased, whereas miR-1296 knockdown increased the expressions of SRPK1 mRNA and protein in HCC cells ( P < 0.05, respectively, Fig.…”

Section: Resultssupporting

confidence: 52%

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MicroRNA-1296 inhibits metastasis and epithelial-mesenchymal transition of hepatocellular carcinoma by targeting SRPK1-mediated PI3K/AKT pathway

et al. 2017

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BackgroundIncreasing evidences demonstrate that miRNAs contribute to development and progression of hepatocellular carcinoma (HCC). Underexpression of miR-1296 is recently reported to promote growth and metastasis of human cancers. However, the expression and role of miR-1296 in HCC remain unknown.MethodsThe levels of miR-1296 in HCC tissues and cells were detected by qRT-PCR. Immunoblotting and immunofluorescence were used for detection of epithelial-to-mesenchymal transition (EMT) progression in HCC cells. Transwell assays were performed to determine migration and invasion of HCC cells. A lung metastasis mouse model was used to evaluated metastasis of HCC in vivo. The putative targets of miR-1296 were disclosed by public databases and a dual-luciferase reporter assay.ResultsWe found that the expression of miR-1296 was reduced in HCC tissues and cell lines, and it was associated with metastasis and recurrence of HCC. Notably, miR-1296 overexpression inhibited migration, invasion and EMT progress of HCCLM3 cells, while miR-1296 loss facilitated these biological behaviors of Hep3B cells in vitro and in vivo. In addition, miR-1296 inversely regulated SRPK1 abundance by directly binding to its 3′-UTR, which subsequently resulted in suppression of p-AKT. Either SRPK1 re-expression or PI3K/AKT pathway activation, at least partially, abolished the effects of miR-1296 on migration, invasion and EMT progress of HCC cells. Furthermore, miR-1296 and SRPK1 expression were markedly correlated with adverse clinical features and poor prognosis of HCC patients. We showed that hypoxia was responsible for the underexpression of miR-1296 in HCC. And the promoting effects of hypoxia on metastasis and EMT of HCC cells were reversed by miR-1296.ConclusionsUnderexpression of miR-1296 potentially serves as a prognostic biomarker in HCC. Hypoxia-induced miR-1296 loss promotes metastasis and EMT of HCC cells probably by targeting SRPK1/AKT pathway.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-017-0675-y) contains supplementary material, which is available to authorized users.

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Section: Resultssupporting

confidence: 52%

“…Previous studies confirmed that SRPK1 predicts poor survival and promotes cell proliferation of HCC through PI3K/AKT signaling [25, 26]. Subsequently, to confirm the biological role of SRPK1 in metastasis and EMT progression, SRPK1 was knocked down by a specific siRNA in HCCLM3 cells ( P < 0.05.…”

Section: Resultsmentioning

confidence: 76%

MicroRNA-1296 inhibits metastasis and epithelial-mesenchymal transition of hepatocellular carcinoma by targeting SRPK1-mediated PI3K/AKT pathway

et al. 2017

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“…Our data showed that SRPK1 was associated with alternative splicing of CHK1 in both cancer cells and tumor tissues. Furthermore, SRPK1 had been reported to associate with hepatocellular carcinoma progression and poor patient survival [38]. Therefore, SRPK1 may mediate CHK1-S mRNA splicing through its downstream splicing factor in HCC.…”

Section: Discussionmentioning

confidence: 99%

Clinical and functional significance of CHK1-S, an alternatively spliced isoform of the CHK1 gene, in hepatocellular carcinoma

Wang

et al. 2020

J. Cancer

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Alternative splicing plays critical roles in many disease processes and splicing dysregulation is a hallmark of cancer. The different splicing isoforms may have significantly different effects on the malignant progression of cancer. Checkpoint kinase 1 (CHK1) is a serine/threonine kinase and regulates DNA damage response. In this study, we measured the expression of an alternative CHK1 transcript (CHK1-S, excluded exon 3) in hepatocellular carcinoma (HCC) tissues. Our results showed that CHK1-S was significantly upregulated in HCC tissues compared with paired adjacent noncancerous hepatic tissues. The levels of full-length CHK1(CHK1-L), CHK1-S and the ratio of CHK1-S/L in tumor tissue were associated with relapse free survival (RFS) of postoperative HCC patients, respectively, but not the levels of CHK1-L, CHK1-S and the ratio of CHK1-S/L in adjacent normal tissue. To further demonstrate the role of CHK1-S in HCC, CCK-8 assays, EdU incorporation assays and colony formation assays were used. The results showed that overexpression of CHK1-S significantly accelerated HCC cell proliferation, compared with CHK1-L. In addition, we found that serine-arginine protein kinase 1 (SRPK1), as an upstream regulator kinase of splicing factor, could upregulate the expression of CHK1-S and its expression level was significantly higher in HCC tumors than the paired normal tissues and was associated with the levels of CHK1-S (P=0.016). In conclusion, our study demonstrated that CHK1-S, acts as an oncogene, which was upregulated and associated with RFS in HCC patients. SRPK1 may mediate its mRNA splicing in HCC. All these data indicated that the expression of CHK1-S would have potential prognostic values and splicing kinase SRPK1 might be developed as therapeutic target in HCC.

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“…The SRPK1-induced PI3K/AKT pathway interacts with miR-1296 [45] ↑SRPK1 was found in hepatocellular cancer cell lines [46] ↑SRPK1 was found in hepatocellular cancer cell lines and promoted proliferation ↓SRPK1 suppressed proliferation in vitro and growth in vivo and in vitro SRPK1 interacts with the PI3K/AKT pathway [47] Esophagus ↑SRPK1 was found in esophageal cancer cell lines and promoted proliferation ↓SRPK1 suppressed proliferation, migration, and invasion and enhanced apoptosis in vitro also suppressed tumor growth in vivo SRPK1 interacts with the TGF-β pathways [48] Pancreas ↑SRPK1 was found in pancreatic cancer cell lines ↓SRPK1 suppressed proliferation and enhanced apoptosis and sensitivity to chemotherapy in vitro SRPK1 interacts with SR proteins and regulates apoptosis [22] SRPK1 interacts with the AKT and MAPK pathways [36] Blood (Leukemia) ↓SRPK1 suppressed proliferation in vitro and tumor growth in vivo, while it enhanced cell cycle arrest, apoptosis and prolonged the survival of animal models in MLL-rearranged AML; ↓SRPK1 switched BRD4 splicing, favoring the production of its long isoform SRPK1 modulates the alternative splicing of BRD4, MYB, and MED24 [65] ↑SRPK1 was found in various myeloid and lymphoid leukemia cell lines ↓SRPK1 was cytotoxic and enhanced apoptosis in vitro SRPK1 interacts with the SR proteins and modulates the expression and splicing of MAP2Ks, VEGF, and FAS [66] ↓SRPK1 suppressed proliferation while it enhanced autophagy and apoptosis in a synergistic fashion with chemotherapy in vitro SRPK1 interacts with SR proteins and modulates the expression of MAP2Ks and VEGF and the splicing of RON [67] ↓SRPK1 suppressed proliferation and enhanced apoptosis in vitro in CML SRPK1 interacts with the PARP-caspase-3 pathway [68] Kidney ↑SRPK1 was found in renal cancer cell lines ↓SRPK1 suppressed proliferation, migration, and invasion in vitro, also tumor growth in vivo SRPK1 interacts with PI3K/AKT pathway [50] Brain (Glioma) ↑SRPK1 was found in glioma cell lines ↓SRPK1 suppressed proliferation, migration, and invasion of glioma cells in vitro while it induced resistance to chemotherapy [51] ↓SRPK1 suppressed tumor growth and apoptosis in vivo, also angiogenesis in vitro and in vivo…”

Section: ↓Srpk1 Suppressed Migration and Invasion In Vitromentioning

confidence: 95%

“…In stomach cancer, high SRPK1 was also found compared to the normal stomach histology [31,[41][42][43][44] and was associated with higher grade, stage, larger tumor size, lymph node metastases, and shorter overall survival [41,43,44]. Liver cancer was also characterized by SRPK1 overexpression, while the latter was correlated with higher stage, larger tumor size, and shorter survival [45][46][47]. In esophageal cancer, high expression of SRPK1 was associated with higher grade, stage, the capacity to metastasize, and shorter overall survival at both univariate and multivariate levels [48].…”

Section: Cancer Type (Primary Location)mentioning

confidence: 99%

Serine-Arginine Protein Kinase 1 (SRPK1) as a Prognostic Factor and Potential Therapeutic Target in Cancer: Current Evidence and Future Perspectives

Nikas

Themistocleous

Paschou

et al. 2019

Cells

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Cancer, a heterogeneous disease composed of tumor cells and microenvironment, is driven by deregulated processes such as increased proliferation, invasion, metastasis, angiogenesis, and evasion of apoptosis. Alternative splicing, a mechanism led by splicing factors, is implicated in carcinogenesis by affecting any of the processes above. Accumulating evidence suggests that serine-arginine protein kinase 1 (SRPK1), an enzyme that phosphorylates splicing factors rich in serine/arginine domains, has a prognostic and potential predictive role in various cancers. Its upregulation is correlated with higher tumor staging, grading, and shorter survival. SRPK1 is also highly expressed in the premalignant changes of some cancers, showing a potential role in the early steps of carcinogenesis. Of interest, its downregulation in preclinical models has mostly been tumor-suppressive and affected diverse processes heterogeneously, depending on the oncogenic context. In addition, targeting SRPK1 has enhanced sensitivity to platinum-based chemotherapy in some cancers. Lastly, its aberrant function has been noted not only in cancer cells but also in the endothelial cells of the microenvironment. Although the aforementioned evidence seems promising, more studies are needed to reinforce the use of SRPK1 inhibitors in clinical trials. major area of research in the field of intratumor heterogeneity, while their presence is associated with cancer recurrence, metastasis, and resistance to chemotherapy [7].Cancer prognosis depends on multiple factors that affect survival. Tumor staging, traditionally performed with the TNM system, is the most important prognostic factor. It refers to the size of the tumor (T), also the extent of its spread to the regional lymph nodes (N) or distant metastatic sites (M) [8,9]. Grading refers to the histologic picture of the tumor, more specifically, how closely it looks compared to the normal tissue it derives from (differentiation) [10,11]. Both the presence of distant metastases (e.g., in lungs, brain, liver, bones) and poor differentiation are associated with a dismal prognosis [9,11]. The molecular subtype of specific cancers is also critical for cancer survival. For instance, breast cancer has diverse intrinsic subtypes-luminal A and B, human epidermal growth factor receptor 2-enriched (HER2-enriched), and basal-like-that directly impact prognosis [12][13][14]. Luminal breast cancers are most commonly hormone-positive, overexpressing estrogen receptors (ER), and are associated with a better prognosis than HER2-enriched or basal-like breast cancers (BLBCs) [12][13][14][15]. BLBCs, which most commonly present with a triple-negative phenotype, have been linked with the worst prognosis and highest metastatic potential of all breast cancer molecular subtypes [13,16,17].Alternative splicing is the process that removes introns and adds exons in various combinations resulting in multiple mRNA products hence protein transcripts. As a result, it maintains the protein diversity and cellular homeostasis [18]. The...

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Serine-arginine protein kinase 1 is associated with hepatocellular carcinoma progression and poor patient survival

Cited by 9 publications

References 28 publications

MicroRNA-1296 inhibits metastasis and epithelial-mesenchymal transition of hepatocellular carcinoma by targeting SRPK1-mediated PI3K/AKT pathway

MicroRNA-1296 inhibits metastasis and epithelial-mesenchymal transition of hepatocellular carcinoma by targeting SRPK1-mediated PI3K/AKT pathway

Clinical and functional significance of CHK1-S, an alternatively spliced isoform of the CHK1 gene, in hepatocellular carcinoma

Serine-Arginine Protein Kinase 1 (SRPK1) as a Prognostic Factor and Potential Therapeutic Target in Cancer: Current Evidence and Future Perspectives

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