Regulation of extracellular and intracellular prolactin on cell proliferation and survival rate through GHR/JAK2/STAT3 pathway in NSCLC

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Styrene increases serum prolactin (PRL) concentration. Hyperprolactinemia is associated with poor prognosis in lung cancer patients, but the mechanism of PRL action is unclear. The aims of this study were to (i) investigate the mechanism of PRL-action receptor in NSCLC cells (ii) measure whether PRL was secreted by NSCLC cells and its stimulatory mechanism in vitro and in vivo. We found that cell proliferation was increased after treatment of a pharmacological dose of PRL in A549 cells, which through up regulation of growth hormone receptor (GHR) and downstream of JAK2/STAT3/VEGF pathway. All NSCLC cells in the present study secreted PRL and expressed GHR, but not PRLR. Inhibition of GHR protein level led to decrease the PRL-induced cell proliferation. PRL was detected in NSCLC cells culture medium. Knockdown of intracellular PRL downregulated JAK2/STAT3 protein activities and GHR and VEGF protein levels. Furthermore, knockdown of intracellular PRL reduced the cell proliferation and the ability of colony-forming. In lung cancer tissues, PRL, GHR and VEGF levels were higher in the tumor tissues than in normal tissues and the protein expressions of these three proteins are positively correlated, respectively. High expression levels of both PRL and GHR cause a poor survival rate in lung cancer patients. Taken together, our results suggested that extracellular and intracellular PRL were involved in cell proliferation through GHR. Combination of in vitro and in vivo results, GHR and PRL are important targets for suppressing NSCLC cell proliferation, which might improve the survival rate in NSCLC patients.