Long Non-coding RNA DLGAP1-AS1 Facilitates Tumorigenesis And Metastasis In Hepatocellular Carcinoma And Its Underlying Molecular Mechanisms

Hepatocellular carcinoma(HCC)is a common lethal malignant tumor,which seriously affects the lives and health of the people.The overall prognosis of HCC is unsatisfactory.The main reasons are the occult onset of HCC,high malignancy,easy recurrence and easy metastasis.Therefore,understudying the molecular mechanism of HCC is expected to elucidate the biological characteristics of HCC and to provide a basis for the development of targeted drug in the future.The JAK/STAT signaling pathway is an evolutionarily conserved signaling pathway activated by various cytokines,interferons,and growth factors,which control cell growth and differentiation.In physiological conditions,the IL-6/JAK/STAT3 signaling pathway initiates and maintains liver regeneration via cyclin D1 and p21.In addition,IL-6/JAK/STAT3 pathway protect liver cells from apoptosis by upregulating anti-apoptotic protein.However,the continuous activation of JAK/STAT3 causes an uncontrollable inflammatory response,leading to the occurrence of chronic inflammatory diseases and promoting the progression of tumor diseases.It has been found that the continuous activation of the IL-6/JAK/STAT3 signaling pathway can promote tumor cell proliferation,survival,invasion and metastasis on the one hand,and on the other hand also inhibit the anti-tumor immune response.However,the mechanism of IL-6/JAK/STAT signaling pathway in the continuous activation of liver cancer is not fully understood.The Wnt/?-Catenin signaling pathway is also a highly conserved signaling pathway that plays an important role in various biological processes,such as embryonic development,organ formation,stem cell maintenance,wound healing,and tissue homeostasis.Wnt signaling pathway affect many pathological processes,especially in cancer and fibrosis.Wnt signaling affects cell division through targeted regulation of cyclin.More and more evidences indicate that abnormal activation of Wnt pathway plays an important role in the development of liver cancer,which contributes the stem cell,drug resistance,tumor progression and metastasis.Long non-coding RNA(lncRNA)is a class of RNA transcripts over 200 nucleotides in length,which has poor or no protein coding capacity.Recently,there is increasing evidence that lncRNAs play a significant role in regulating many processes in diseases,including liver cancer and other cancers.LncRNA can affect immune response,liver regeneration and redox signals,and plays a key role in regulating liver microenvironment and chronic liver disease.The dysregulation of lnc RNA will lead to chronic hepatitis,liver hyperplasia and oxidative stress,and eventually lead to the occurrence and development of liver cancer.It has been found that lnc RNA can promote the proliferation of liver cancer,change the metabolic state of tumor cells,improve the stem cell characteristics of tumor cells,and promote invasion and metastasis.Therefore,study the impact of lncRNA on the biological behavior of liver cancer provides a theoretical basis for elucidating the molecular mechanism of liver cancer growth and metastasis,and is helpful for future research and development of targeted drugs.The research of this topic revolves around the clinical problem of liver cancer,that is,the characteristics of rapid tumor growth and metastasis,combined with the current research hot spot,that is,long-chain non-coding RNA plays an important role in the malignant progression of tumors.And we propose a scientific hypothesis that the growth and metastasis of liver cancer may be affected the regulation of certain long non-coding RNAs activates signaling pathways.In this study,we found that long-chain non-coding RNA(DLGAP1-AS1)is highly expressed in liver cancer cells and tissues,and its high expression indicates that liver cancer patients have a shorter overall survival time.Then we used cell biology experiments to prove that DLGAP1-AS1 can enhance the growth of liver cancer and promote tumor cell epithelial-mesenchymal transition.Mouse animal experiments confirmed that DLGAP1-AS1 promotes the growth of liver cancer subcutaneous tumors and increases the number of lung metastases.Further molecular biology experiments found that DLGAP1-AS1,by binding to miR-26a/b-5p,on the one hand,relieves miRNA from inhibiting IL-6,up-regulates the expression of IL-6,and activates the JAK2/STAT3 signaling pathway;on the other hand DLGAP1-AS1 binds to miR-26a/b-5p,relieves miRNA from inhibiting CDK8 and LRP6,activates the Wnt/b-catenin signaling pathway,and ultimately promotes the growth and metastasis of liver cancer.Our results show that DLGAP1-AS1 is involved in the regulation of tumorigenesis and metastasis in and out of liver cancer,suggesting that DLGAP1-AS1 may become a potential target for the treatment of liver cancer.