title: LARP7 is a potential tumor suppressor gene in gastric cancer.
abstract: We previously reported frequent truncating mutations of the RNA-binding protein gene, La ribonucleoprotein domain family, member-7 (LARP7) in gastric cancers (GCs) with frequent microsatellite instability. LARP7 negatively regulates positive transcription elongation factor-b (p-TEFb) by binding to and stabilizing 7sk RNA. p-TEFb has been linked to proliferation and de-differentiation in various tissues. Therefore, we reasoned that loss of LARP7 may contribute to gastric tumorigenesis. In this study, we evaluated LARP7 mRNA expression in 18 GCs, their corresponding non-neoplastic gastric tissues (N(GC)), and 18 normal gastric tissues from healthy individuals (N(N)). We also assessed the effects of transient small interfering (siRNA)-mediated LARP7 knockdown in immortalized non-neoplastic gastric epithelial cells. LARP7 mRNA was significantly decreased in GCs (median 2.5) relative to N(N)s (median 14.9, P<0.01) as well as relative to their corresponding N(GC)s (median 8.1, P<0.01). Transfection of an siRNA directed against LARP7 (anti-LARP7 siRNA) into non-neoplastic gastric epithelial cells decreased 7sk levels by 72% relative to a control siRNA (P<0.01). Furthermore, anti-LARP7 siRNA transfection increased cell proliferation by 23% (P<0.01) and cell migration by 22% (P<0.001) relative to control siRNA transfection. Taken together, these findings suggest that LARP7 downregulation occurs early during gastric tumorigenesis and may promote gastric tumorigenesis via p-TEFb dysregulation.
authors.affiliation: Division of Gastroenterology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Yulan
authors.initials: Y
authors.lastname: Cheng
authors.forename: Zhe
authors.initials: Z
authors.lastname: Jin
authors.forename: Rachana
authors.initials: R
authors.lastname: Agarwal
authors.forename: Ke
authors.initials: K
authors.lastname: Ma
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.forename: Soibrahim
authors.initials: S
authors.lastname: Ibrahim
authors.forename: Alexandru V
authors.initials: AV
authors.lastname: Olaru
authors.forename: Stefan
authors.initials: S
authors.lastname: David
authors.forename: Hassan
authors.initials: H
authors.lastname: Ashktorab
authors.forename: Duane T
authors.initials: DT
authors.lastname: Smoot
authors.forename: Mark D
authors.initials: MD
authors.lastname: Duncan
authors.forename: David F
authors.initials: DF
authors.lastname: Hutcheon
authors.forename: John M
authors.initials: JM
authors.lastname: Abraham
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Meltzer
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Mori
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D016022:Case-Control Studies; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D015536:Down-Regulation; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism / Q000473:pathology; D055785:Gene Knockdown Techniques; D016147:Genes, Tumor Suppressor; D006801:Humans; D008297:Male; D008875:Middle Aged; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D012261:Ribonucleoproteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: C528908:Larp7 protein, human; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D012261:Ribonucleoproteins; D042925:Positive Transcriptional Elongation Factor B