| Background Cancer is a universal major problem that threats global human public health and life quality,in which lung cancer has the highest incidence and mortality rate in all the populations.Prostate cancer and cervical cancer are the two commonly diagnosed cancers in males and females,respectively.Osteosarcoma,the most common primary tumor of bone,occurs most frequently in children and adolescents.The carcinogenesis mechanisms and therapeutic regimens of these cancers have become hotspots for further researches.ATP citrate lyase(ACLY)is the vital metabolic enzyme that converts citrate into acetyl-Co A and initiates de novo biosynthesis for fatty acid and cholesterol.The aberrant expression of ACLY in several types of cancer has been long recognized,and its inhibition is known to induce proliferation arrest in cancer cells both in vitro and in vivo.micro RNAs(mi RNAs)are a class of endogenous non-coding small RNA,which function at posttranscriptional level as negative regulators of gene expression,and play an important role in tumor biology,including initiation,proliferation,invasion,metastasis,and cellular metabolism.So far,the potential role of mi RNAs in the regulation of ACLY expression remains unidentified.Our study aims to seek for the underlying mi RNA that is capable of regulating ACLY in various malignant tumors.Methods and Results Here,clinical samples of 117 osteosarcoma,135 prostate cancer,129 cervical cancer and 150 lung cancer along with the corresponding normal adjacent tissues were enrolled in our investigation.In general,higher ACLY protein levels were found in the four tumors compared to the normal counterparts by using the immunohistochemistry staining.Particularly,a different expression pattern of ACLY protein was characterized in the four pathological types of osteosarcoma,which could used to make the differential diagnosis of different osteosarcoma subtypes to some extent;in prostate cancer,cervical cancer and lung cancer,we confirmed a remarkable raise of the ACLY expression along with the accumulation of the pathological stages,in which higher ACLY levels were found in poor differentiated tumors;in cervical cancer and lung cancer,the expression of ACLY increased with the ascending rank of the clinical TNM stage,suggesting that ACLY could be regarded as a promising pro-oncogenic factor in these neoplasms.With the application of Bioinformatics,in situ hybridization and Real-time PCR,we demonstrated that mi R-22 was responsible for inhibiting the ACLY protein expression through binding to the 3'-untranslated region of ACLY m RNA.In vitro verifications including the luciferase activity,MTT assay,transwell assay,flowcytometry were performed on the four eternal cancer cell lines after the transfection of the mi R-22 mimic or inhibitor.And we discovered that mi R-22 attenuated cancer cell proliferation and invasion,as well as promoted cell apoptosis by an ACLY-dependent way.Bioluminescence imaging was conducted on tumor-bearing mice and agomi R of mi R-22 was introduced in the assessment of cancer treatment.In the four tumorigenic models,along with the loss of the ACLY expression,the mi R-22-treated mice developed rather smaller tumors,less probabilities of distant metastasis and survived fairly longer lives.To make further exploration,lipid staining was performed,and the protein and m RNA expressions of FASN and HMGCR were detected both in vitro and in vivo.It was speculated that the mechanism of the anti-tumor effects of mi R-22 may be trigger by the downregulation of the ACLY-mediated de novo lipogenesis and the reduced expression of the downstream lipogenic enzymes of ACLY.Conclusion Our findings provide the first evidence that ACLY is directly targeted by mi R-22.In osteosarcoma,prostate,cervical and lung cancer,the regulation of mi R-22/ACLY axis leads to lipogenesis disorders and the suppression of tumor growth and metastasis,which create novel perspectives in cancer therapeutics. |
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