Abstract
PurposeG-protein coupled receptor (GPR 34) has been found to play important roles in some cancers and regulates the proliferation, apoptosis, and migration of these cancer cells. However, the mechanisms underlying how GPR34 functions to regulate growth and proliferation of colorectal cancer cells remains to be clarified.MethodsWe employed stable GPR34 knockdown LS174T cell models, GPR34 Mab blocking, a CCK-8 kit, and a colony formation assay to characterize the effect of GPR34 on the proliferation of LS174T in vitro and xenograft tumor growth in vivo. The mRNA level of GPR34 was detected by RT-PCR in tumor tissues and adjacent normal tissues from 34 CRC patients.ResultsBased on RT-PCR results, GPR34 exhibited high level in tumor samples compared with adjacent normal samples. Increased expression of GPR34 is more associated with poor prognosis of CRC as shown in The Cancer Genome Atlas (TCGA) dataset by Kaplan–Meier survival analysis. Furthermore, we showed that GPR34 knockdown inhibited the proliferation of LS174T colon cancer cells and related xenograft tumor growth. Searching for the distinct molecular mechanism, we identified several contributors to proliferation of LS174T colon cancer cells: PI3K subunits/PTEN, PDK1/AKT, and Src/Raf/Ras/ERK. GPR34 knockdown inhibited the proliferation of LS174T cells by upregulating expression of PTEN, and downregulating expression of PI3K subunits p110-beta.ConclusionOur findings provide direct evidence that GPR34 regulates the proliferation of LS174T cells and the growth of LS174T tumor xenografts by regulating different pathways. High expression of GPR34 mRNA could then be used to predict poor prognosis of CRC.
Highlights
G-protein coupled receptor 34 (GPR34) is a 7-transmembrane receptor that regulates key biological functions including cellular growth, motility, apoptosis, and gene transcription, and appears to be involved in the progression of several cancers [1,2,3,4,5,6,7,8,9]
The mRNA-seq expression datasets collected from the The Cancer Genome Atlas (TCGA) database contained 208 patients diagnosed with colorectal cancer, and consisted of 112 men and 96 women
We examined the potential relationships between the mRNA levels of GPR34 in CRC and its clinical parameters
Summary
G-protein coupled receptor 34 (GPR34) is a 7-transmembrane receptor that regulates key biological functions including cellular growth, motility, apoptosis, and gene transcription, and appears to be involved in the progression of several cancers [1,2,3,4,5,6,7,8,9]. We identified GPR34/PI3K/AKT as an alternative pathway that may mediate p185Bcr/Ablinduced transformation and leukemogenesis These studies indicated that GPR34 plays its pro-proliferation role by effecting different PI3K subunits and AKT pathways [5, 8]. This required us to perform a more in-depth investigation of the underlying mechanisms of GPR34/PI3K in colorectal cancer cell proliferation. We investigated the effects of GPR34 knockdown on proliferation of LS174T colon cancer cells, as well as PI3K subunits/AKT and ERK expression, with the aim of evaluating whether the expression of GPR34 may regulate the growth and proliferation of colon cancer cells, and exploring the details of the underlying mechanisms. We evaluated the GPR34 mRNA level of 34 CRC tumor tissue using RT-PCR
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