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Variant 2 of KIAA0101, antagonizing its oncogenic variant 1, might be a potential therapeutic strategy in hepatocellular carcinoma.

ABSTRACT: Hepatocellular carcinoma (HCC) is one of the most lethal malignant tumors worldwide and effective therapies, including molecular therapy, remain elusive. Our previous work demonstrates that oncogenic KIAA0101 transcript variant (tv) 1 promotes HCC development and might be a HCC therapeutic target. However, the function of another KIAA0101 variant, KIAA0101 tv2, remains unknown. In this study, we reported that KIAA0101 tv2 was highly expressed in adjacent non-tumorous liver tissues (NTs) compared to HCC tissues. In vivo and in vitro results showed that KIAA0101 tv2 decreased cell survival, colony formation, tumor xenografts, migration, and invasion, as well as induced cell cycle arrest and apoptosis. Interestingly, it could inhibit the function of KIAA0101 tv1 by partially down-regulating KIAA0101 tv1, acting similar to KIAA0101 tv1 short hairpin RNA (shRNA). Further studies illustrated that KIAA0101 tv2 could increase the activity of p53 by competing with KIAA0101 tv1 for P53 binding. In conclusion, KIAA0101 tv2 exerts anti-tumor activity in HCC and acts as an endogenous competitor of tumor-associated KIAA0101 tv1. KIAA0101 tv2 has a potential to work as a therapeutic drug targeting the KIAA0101 tv1 in HCC.

SUBMITTER: Liu L

PROVIDER: S-EPMC5546456 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Variant 2 of KIAA0101, antagonizing its oncogenic variant 1, might be a potential therapeutic strategy in hepatocellular carcinoma.

Liu Lijuan L Liu Youyi Y Chen Xiaobei X Wang Miao M Zhou Yan Y Zhou Ping P Li Wenxin W Zhu Fan F

Oncotarget 20170701 27

Hepatocellular carcinoma (HCC) is one of the most lethal malignant tumors worldwide and effective therapies, including molecular therapy, remain elusive. Our previous work demonstrates that oncogenic KIAA0101 transcript variant (tv) 1 promotes HCC development and might be a HCC therapeutic target. However, the function of another KIAA0101 variant, KIAA0101 tv2, remains unknown. In this study, we reported that KIAA0101 tv2 was highly expressed in adjacent non-tumorous liver tissues (NTs) compared ...[more]

PMID: 28410205

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Project description:Immunosuppressive tumor microenvironment in hepatocellular carcinoma (HCC) is critical in tumor development. C-type (Ca2+ -dependent) lectin (CLEC) receptors, essential in innate pattern recognition, have potential regulatory effects on immune cell trafficking and modulatory effects on cancer cell activity. However, information on the expression and prognostic value of CLECs in HCC is scanty. Herein, we explored the potential role of CLECs in HCC based on TCGA, ONCOMINE, GEPIA, UALCAN, cBioPortal, Metascape, TRRUST, and TIMER databases. Results demonstrated a significantly higher mRNA level of CLEC4A and CLEC4L in HCC tissues than normal liver tissues. Contrarily, we found significantly low CLEC4G/H1/H2/M expression in HCC tissues. The IHC analysis revealed the following: Absence of CLEC4A/J/K/M in normal and liver cancer tissues; high CLEC4C expression in HCC tissues; low expression and zero detection of CLEC4D/E/H1/H2/L in HCC tissues and normal tissues, respectively. And the HepG2 and LX-2 were used to verify the expression level of CLEC4s via qRT-PCR in vitro. Furthermore, the expression of CLEC4H1 (ASGR1) and CLEC4H2 (ASGR2) exhibited a significant relation to clinical stages. However, the expression of CLEC4A, CLEC4D, CLEC4E, CLEC4J (FCER2), CLEC4K (CD207), CLEC4G, CLEC4H1, CLEC4M, and CLEC4H2 decreased with tumor progression. Patients expressing higher CLEC4H1/H2 levels had longer overall survival than patients exhibiting lower expression. Moreover, CLEC4A/D/E/J/K/G/H1/M/H2 had significant down-regulated levels of promoter methylation. The expression level of CLEC4s was correlated with the infiltration of B cells, CD8 + T cells, CD4 + T cells, macrophage cells, neutrophil cells, and dendritic cells. Functional analysis revealed the potential role of CLECL4s in virus infection, including COVID-19. Also, hsa-miR-4278 and hsa-miR-324-5p, two potential miRNA targets of CLEC4s, were uncovered. This article demonstrates that CLEC4 is crucial for the development of HCC and is associated with infiltration of various immune cells, providing evidence for new immunotherapy targets in HCC.

Dataset Information

Variant 2 of KIAA0101, antagonizing its oncogenic variant 1, might be a potential therapeutic strategy in hepatocellular carcinoma.

Publications

Variant 2 of KIAA0101, antagonizing its oncogenic variant 1, might be a potential therapeutic strategy in hepatocellular carcinoma.

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