Transforming growth factor‐β signaling enhancement by long‐term exposure to hypoxia in a tumor microenvironment composed of Lewis lung carcinoma cells

Abstract

Transforming growth factor‐β (TGF‐β) is a potent growth inhibitor in normal epithelial cells. However, a number of malignant tumors produce excessive amounts of TGF‐β, which affects the tumor‐associated microenvironment by furthering the progression of tumorigenicity. Although it is known that the tumor‐associated microenvironment often becomes hypoxic, how hypoxia influences TGF‐β signaling in this microenvironment is unknown. We investigated whether TGF‐β signaling is influenced by long‐term exposure to hypoxia in Lewis lung carcinoma (LLC) cells. When the cells were exposed to hypoxia for more than 10 days, their morphology was remarkably changed to a spindle shape, and TGF‐β‐induced Smad2 phosphorylation was enhanced. Concomitantly, TGF‐β‐induced transcriptional activity was augmented under hypoxia, although TGF‐β did not influence the activity of a hypoxia‐responsive reporter. Consistently, hypoxia influenced the expression of several TGF‐β target genes. Interestingly, the expressions of TGF‐β type I receptor (TβRI), also termed activin receptor like kinase‐5 (ALK5), and TGF‐β1 were increased under the hypoxic condition. When we monitored the hypoxia‐inducible factor‐1 (HIF‐1) transcriptional activity by use of green fluorescent protein governed by the hypoxia‐responsive element in LLC cells transplanted into mice, TGF‐β‐induced Smad2 phosphorylation was upregulated in vivo. Our results demonstrate that long‐term exposure to hypoxia might alter responsiveness to TGF‐β signaling and affected the malignancy of LLC cells.

Requirements of LEFTY and Nodal overexpression for tumor cell survival under hypoxia in glioblastoma

“…A similar finding was also observed in Lewis lung carcinoma cells, where long-term exposure to hypoxia elevated TGF-β-mediated R-Smads including Smad2, thereby modulating transcriptional activity upon TGF-β family stimulation. 40 Given our results of increased LEFTY, but not Nodal, promoter HIF-1 is a major hypoxia-induced transcriptional regulator of many genes. The inducible subunit, HIF-1α, is mainly regulated by oxygen-dependent hydroxylation of two proline residues.…”

Ovarian Carcinoma-Associated Mesenchymal Stem Cells Arise from Tissue-Specific Normal Stroma

“…One hallmark of the TME which impacts normal MSC morphology, proliferation, and differentiation is hypoxia . Hypoxia is known to increase TGF‐β signaling and GATA4 expression, genes upregulated in CA‐MSCs . CA‐MSCs demonstrated higher transcript and protein levels of hypoxia inducible factor alpha (HIF1α) and indirect cancer stimulation induced HIF1α expression in OM MSCs (Fig.…”

Subtoxic dose of lithium cobalt oxide nanosheets impacts critical molecular pathways in trout gill epithelial cells

“…6d) and are known to be hypoxia responsive. 59,62,63 To directly compare the responses of the toxic and subtoxic doses (rather than their degree of change compared to control), we first identified genes showing highly significant differences in their expression levels between the toxic and subtoxic doses at each of the time points. We then used these genes for pathway enrichment.…”