Calreticulin: A Player in Metastatic Lung Cancer

Background and Aim: Lung cancer is considered as one of most frequentcancers in the world causing high morbidity and mortality. Non-smallcell lung cancer (NSCLC) and small cell lung cancer (SCLC) compromise,80% and 20% of lung carcinoma, respectively. Although many factorssuch as Tobacco, asbestos, and genetic factors have been associated withlung cancer, the mechanism leading to the development of metastaticadenocarcinoma is not clear. Our recent data on genetically modifiedmouse model, overexpressing calreticulin under Tie2 promoter showeddevelopment of metastatic lung adenocarcinoma in these mice.Calreticulin (CRT) is a ubiquitously expressed protein in mammaliancells, with both calcium binding and chaperone activity. CRT is involvedin quality control process during the folding and maturation of protein inendoplasmic reticulum.Methods: Total RNA were isolated from lungs of transgenic mouse line(Tie2-CRT) that develop cancer and wild type mice using Trizol reagent.Gene expression was examined using microarray technique. Lentiviraldelivery for shRNA was used to silence the long-non-coding RNA in lungtumor cell lines isolated from the Tie2-CRT mice. To identify down streamtargets of Malat-1, cells infected with shRNA of Malat-1 or scrambledcontrol were used to isolate total RNA. RNA sequencing were performedand genes affected were identified.Results: Microarray analysis of lung tissue from Tie2-CRT mice as comparedto the wild type mice, showed a significant increase in a number of long non-coding RNAs. One of these long non coding RNA (LncRNA) knownas Metastasis Associated Lung Adenocarcinoma Transcript-1 (Malat-1)has been implicated in the development of metastatic lung cancer.Malat-1 is a novel Lnc RNA that is localized to nucleus. Furthermore,its 3’ end can be spliced to form tRNA like structure called mascRNAthat translocate to cytoplasm. Our data illustrate the involvement of thisLnc RNA in the increased rate of tumor cell migration and altered cellcycle. The exact targets of this Lnc RNA are not known. Using RNA-Seq.analysis of tumor cells after knockdown of Malat-1, we illustrate changesin cluster of genes involved in cell proliferation and migration.Conclusion: Our data identifies Malat-1 as one of LncRNA upregulatedin mouse lung cancer like Human lung adenocarcinoma. We alsoidentify a number of genes which are targets of this LncRNA and assistin its metastatic effect.

کلیدواژه ها:

Long non-coding RNA ، Lung Cancer ، Cell proliferation ، Cell migration ، Metastasis