Growth hormone is increased in the lungs and enhances experimental lung metastasis of melanoma in DJ-1 KO mice

Abstract

BackgroundGrowth hormone (GH) mainly serves an endocrine function to regulate somatic growth, but also serves an autocrine function in lung growth and pulmonary function. Several recent studies have demonstrated the role of autocrine GH in tumor progression in some organs. However, it is not clear whether excessive secretion of GH in the lungs is related to pulmonary nodule formation.MethodsFirstly, the lung tissues dissected from mice were used for Western blotting and PCR measurement. Secondly, the cultured cells were used for examining effects of GH on B16F10 murine melanoma cells. Thirdly, male C57BL/6 mice were intravenously injected with B16F10 cells and then subcutaneously injected with recombinant GH twice per week for three weeks. Finally, stably transfected pool of B16F10 cells with knockdown of growth hormone receptor (GHR) was used to be injected into mice.ResultsWe found that expression of GH was elevated in the lungs of DJ-1 knockout (KO) mice. We also examined the effects of GH on the growth of cultured melanoma cells. The results showed that GH increased proliferation, colony formation, and invasive capacity of B16F10 cells. In addition, GH also increased the expression of matrix metalloproteinases (MMPs) in B16F10 cells. Administration of GH in vivo enhanced lung nodule formation in C57/B6 mice. Increased lung nodule formation in DJ-1 KO mice following intravenous injection of melanoma cells was inhibited by GHR knockdown in B16F10 cells.ConclusionsThese results indicate that up-regulation of GH in the lungs of DJ-1 KO mice may enhance the malignancy of B16F10 cells and nodule formation in pulmonary metastasis of melanoma.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2898-5) contains supplementary material, which is available to authorized users.

Excess growth hormone suppresses DNA damage repair in epithelial cells

“…GH-treated cells demonstrate increased capacity for anchorage-independent growth, consistent with our in vivo results showing increased metastatic potential of colon cells in the presence of high-circulating GH. Others have shown that high GH increased murine pulmonary melanoma metastases (78). These prometastatic effects may be attributed to both GH-mediated DDR suppression and EMT activation (24).…”

Growth Hormone Upregulates Melanocyte-Inducing Transcription Factor Expression and Activity via JAK2-STAT5 and SRC Signaling in GH Receptor-Positive Human Melanoma

“…Further, we and others have shown a direct effect of GH–GHR action in upregulating expression of ATP-cassette-containing (ABC) multidrug efflux pumps such as ABCB1, ABCC1, ABCC2, and ABCG2 in melanoma [21] as well as in breast cancer [22]. Increased GH production in other tissues, such as lungs, has been found to guide lung metastasis of B16F10 melanoma xenografts in DJ1-KO mice [23]. Therefore, it appears that the GH–GHR pair is harnessed to particularly evade therapeutic challenges by advanced melanoma tumors.…”

Growth Hormone Upregulates Mediators of Melanoma Drug Efflux and Epithelial-to-Mesenchymal Transition In Vitro and In Vivo

“…Previously, we had reported that not only do melanoma cells overexpress GHR but also that targeting GHR in human melanoma cells attenuates tumor progression, EMT induction, drug efflux and more importantly, sensitizes these cells to chemotherapy in vitro [57,58]. Additionally, enhanced metastasis of mouse melanoma cells to the lungs in response to locally elevated GH levels in DJ-1 knockout mice was recently reported and confirms a role of GHR in melanoma metastases [4]. Our current study provides a first in vivo validation to our earlier in vitro mechanistic observations on the role of GH in melanoma chemoresistance.…”

“…Accumulating evidence implicates growth hormone (GH) in the development and progression of a wide range of malignancies [1][2][3][4][5][6][7], including breast [8][9][10][11][12][13][14][15], prostate [16,17], colorectal [18,19], glioma [20], pancreatic [21], thyroid [22], liver [23] and endometrial cancers [24,25]. GH is a peptide hormone produced by pituitary somatotrophs and acts on multiple tissues including bone, muscle, fat, liver, pancreas, heart, thymus and kidney.…”