Gene Expressions for Signal Transduction under Acidic Conditions

Our plain-English summary of Gene Expressions for Signal Transduction under Acidic Conditions, by T. Fukamachi, S. Ikeda, X. Wang, et al (Genes, 2013).

The study

• Authors: T. Fukamachi, S. Ikeda, X. Wang, H. Saito, M. Tagawa, H. Kobayashi
• Journal: Genes
• Published: 2013;4(1):65-85
• Cited by: 9 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Although it is now well known that some diseased areas, such as cancer nests, inflammation loci, and infarction areas, are acidified, little is known about cellular signal transduction, gene expression, and cellular functions under acidic conditions. Our group showed that different signal proteins were activated under acidic conditions compared with those observed in a typical medium of around pH 7.4 that has been used until now. Investigations of gene expression under acidic conditions may be crucial to our understanding of signal transduction in acidic diseased areas. In this study, we investigated gene expression in mesothelioma cells cultured at an acidic pH using a DNA microarray technique. After 24 h culture at pH 6.7, expressions of 379 genes were increased more than twofold compared with those in cells cultured at pH 7.5. Genes encoding receptors, signal proteins including transcription factors, and cytokines including growth factors numbered 35, 32, and 17 among the 379 genes, respectively. Since the functions of 78 genes are unknown, it can be argued that cells may have other genes for signaling under acidic conditions. The expressions of 37 of the 379 genes were observed to increase after as little as 2 h. After 24 h culture at pH 6.7, expressions of 412 genes were repressed more than twofold compared with those in cells cultured at pH 7.5, and the 412 genes contained 35, 76, and 7 genes encoding receptors, signal proteins including transcription factors, and cytokines including growth factors, respectively. These results suggest that the signal pathways in acidic diseased areas are different, at least in part, from those examined with cells cultured at a pH of around 7.4.

In plain English

This was a laboratory study of cells grown in dishes. It did not study people, and asbestos is not mentioned in the article. The authors grew H2052, a human cell line they call mesothelioma cells, at mildly acidic pH 6.7 or at pH 7.5. They used a DNA microarray to measure the expression (RNA levels) of about 24,000 genes after 2, 5 and 24 hours. After 24 hours at pH 6.7, 379 genes showed more than twofold higher expression and 412 more than twofold lower expression than at pH 7.5. Of the 379, 35 coded for receptors, 32 for signal proteins including transcription factors, and 17 for cytokines including growth factors; 78 had unknown functions. Across all time points, 693 genes were up-regulated and 856 down-regulated more than twofold at least once. In an esophageal cancer cell line, five of six rechecked genes showed higher expression at acidic pH; TNFRSF9 did not. Other cancer cell lines responded differently. The authors concluded that even a small pH drop changes gene expression, and cautioned that their data may apply only to mesothelioma cells.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) cell culture experiment using DNA microarray, with real-time quantitative PCR checks of selected genes
• Who was studied: The microarray used human cell line H2052, described in the Methods as a mesothelial cell line and elsewhere as mesothelioma cells. Four other human cancer cell lines were used to recheck six genes: TE-11 esophageal cancer, HT-29 colon adenocarcinoma, HepG2 hepatocellular carcinoma and BxPC3 pancreatic ductal adenocarcinoma. The work was done at Chiba University and Chiba Cancer Center Research Institute, Japan. Dates of the experiments are not given.
• Exposure: Acidic culture medium (pH 6.7) compared with pH 7.5 medium, for 2, 5 and 24 hours. No asbestos or other fiber exposure was studied.
• Main results:
  • In H2052 cells, expression of 379 genes was more than twofold higher after 24 hours at pH 6.7 than at pH 7.5.
  • Of the 379 genes with increased expression, 35 encoded receptors, 32 encoded signal proteins including transcription factors, and 17 encoded cytokines including growth factors. The functions of 78 were unknown.
  • In H2052 cells, expression of 412 genes was more than twofold lower after 24 hours at pH 6.7. These included 35 receptor genes, 76 signal protein genes (including transcription factors) and 7 cytokine genes (including growth factors).
  • After 2 hours at pH 6.7, expression of 260 genes was more than twofold higher. For 223 of these 260, expression fell again by 24 hours.
  • Across all time points in the mesothelioma cells, 693 genes were up-regulated and 856 were down-regulated more than twofold at acidic pH.
  • Earlier studies reported that some genes rise under acid. For these genes, this study found expression ratios at pH 6.7 compared with pH 7.5 of 2.52 for IL-8, 1.90 for MMP-9 and 1.12 for VEGF.
  • In TE-11 esophageal cancer cells, expression of IL-32, AREG, ERBB3, ATP6V0D2 and DMGDH increased after 24 hours at acidic pH. TNFRSF9 expression did not increase.
  • IL-32 expression increased at acidic pH in HT-29, HepG2 and BxPC3 cells. Other genes responded differently from one cell line to another.
• The authors' conclusion: The authors concluded that acidification affects gene expression even when the pH change is small. They suggested that signal pathways in acidic diseased areas differ, at least in part, from those seen in cells cultured at around pH 7.4.
• Limitations the authors state:
  • Because gene expression patterns differed between cell types, the authors stated their data may apply only to mesothelioma cells.
  • mRNA levels are not proportional to protein (enzyme) levels, so protein measurements would be needed.
  • The authors assumed that a more than twofold change was meaningful. They chose this cutoff because PCR measurements of low-copy mRNA had standard deviations close to 50%.
  • The meaning of short-lived increases in gene expression is unclear.

Topics

Medical terms in this study, explained in our Lexicon: Inflammation, Mesothelioma, Cytokine.

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