PIM1 Gene Editing    

Proviral integration site for Moloney murine leukemia virus (PIM) is a gene that was identified when its expression was noted to be up-regulated by proviral insertion in murine virus-induced T-cell lymphomas. The PIM kinase family consists of three constitutively active serine/threonine kinases, PIM1, PIM2 and PIM3, which are associated with diverse human malignancies including leukemias and lymphomas, as well as hepatic, pancreatic, oral and prostate cancers. PIM1 kinase is an attractive molecular target for cancer pharmacotherapy because it enhances the transforming potential of oncogenes. For example, Pim1 accelerates Myc-initiated lymphomagenesis and prostate cancer development in mouse models.

PIM1 and Human Cancer Diseases

In addition to being associated with murine leukemia, alterations in PIM1 signaling have been found in various human tumor diseases too. In hematologic malignancies, PIM1 expression is associated with poor prognosis in various leukemias, mantle cell lymphoma and diffuse large B-cell lymphoma. In solid tumors, overexpression of PIM1 has been detected in bladder cancer (with higher levels in invasive than in non-invasive cancers) and in prostate cancer specimens, where it was also associated with poor prognosis and therapy response. In head and neck cancer, PIM1 was highly expressed in more advanced stages and associated with poor prognosis and lymph node metastasis. Interestingly, PIM1 was also found as a tumor-associated antigen in blood from colorectal cancer patients and has been proposed as a sensitive novel biomarker for this disease. Contrary to these findings, a significant downregulation of PIM1 mRNA was found in primary non-small-cell lung cancer and PIM1 was even further suppressed in lymph node metastases compared with nodal negative tumors. PIM1 was also reported to contribute to radio- and chemotherapy resistance in prostate, pancreatic, head and neck or lung cancer, which confirms the oncogenic properties in modulating hypoxia response or apoptosis signaling in tumor cells.

Targeting PIM1 for Inhibition of Cancer Stem Cells

Increasing evidence has shown the functions of PIM1 in stem cells, including embryonic, hematopoietic, mesenchymal, cardiac and prostate stem cells. In mice, Pim1 expression is induced by STAT3 and leukemia inhibitory factor (LIF) in embryonic stem (ES) cells at the transcriptional level. Therefore, the elevated Pim1 promotes the self-renewal ability of ES cells. PIM1 is essential to prostate stem and cancer stem cells as well. The previous study further identified the essential role of PIM1 in prostate tumor initiation through cancer stem-like cells. As PIM1 has great potential to induce cancer stem cell properties to accelerate prostate cancer progression, targeting PIM1 in cancer stem cells using selective inhibitors may provide a new avenue for treatment of aggressive prostate cancer. The new generation of the PIM1 inhibitor, TP-3654, was screened as the lead compound targeting PIM1 kinase. Using the PC3 cell-derived xenograft model, oral gavage at a dose of 200 mg/kg of TP-3654 significantly decreased the growth of tumors. However, further signaling analysis of cancer stem cells affected by TP-3654 is lacking. AZD1208 is another newly screened highly selective inhibitor that decreases Myc/PIM1 graft tumor growth. In particular, combined with radiation treatment and upregulation of p53, AZD1208 showed more efficiency in the inhibition of prostate cancer cell growth. Whether AZD1208 can inhibit PIM1-mediated cancer stem cell proliferation, expansion and cell reprogramming by targeting Myc remains to be clarified.

Figure 1. PIM1 signaling pathways are associated with stem/cancer stem cells in the prostate. (Xie Y, Bayakhmetov S. 2016)

PIM1 Gene Editing Services

CRISPR/Cas9 Platform^CB, one of the leading biotechnological companies specializing in gene editing, is dedicated to offering comprehensive CRISPR/Cas9 gene-editing services to a wide range of genomics researchers. Based on our platform, we can help you effectively PIM1 gene deleted, inserted or point mutated in cells or animals by CRISPR/Cas9 technology.

• PIM1 Gene Knockout: We offer PIM1 gene knockout cell line and knockout animal model generation service with high quality. Typically, we develop CRISPR-mediated gene editing cell lines including HEK239T, Hela, HepG2, U87, but we can use other cell lines according to your requirements. Our one-stop KO animal model generation service covers from sgRNA design and construction, pronuclear microinjection to Founders genotyping and breeding.
• PIM1 Gene Knockin: CRISPR/Cas9 Platform^CB provides the one-stop PIM1 knock-in cell line and knockout animal model generation services, including point mutation and gene insertion. Our expert staff has succeeded in dozens of PIM1 knock-in cell line generation projects, including stem cells, tumor cells and even difficult-to-handle cells. We also have extensive experience in incorporating CRISPR/Cas9 technology into animal models, which have been fully recognized by our clients.

If you have any questions, please feel free to contact us.

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