Table 1 |.

Molecular actions of GH in human cancers

Molecular action	Effect	Cancer type	Refs.
Oncogenesis and tumour microenvironment
GH is a p53 target and in turn blocks p53 by a negative feedback loop	Tumour initiation	Colon cancer	158
GH induces DNA damage and suppresses DNA damage repair in normal colon tissue	Tumour initiation	Colon cancer	156,157,198
GH resistance reduces number and size of neoplasms in C3(1)/Tag-GHRKO mice	Tumour initiation	Breast cancer, prostate cancer	202,203
GH deficiency suppress DMBA-induced tumour development	Tumour initiation	Breast cancer	204
bGH mice have a higher DEN-induced hepatoma incidence while lit/lit (Ghrhr-knockout) mice have a lower one	Tumour initiation	Liver cancer	205,206
GH supplementation enables MNU-induced tumours in GH-deficient rats; tumours regress on GH withdrawal	Tumour initiation	Breast cancer	175
GH stabilizes hTERT through αCP1 and αCP2	Tumour initiation	Breast cancer	207
GH supports spontaneous neoplastic growth with age	Tumour initiation	Liver cancer	208
GH expression in mammary epithelia promotes oncogenic transformation via HOXA1	Tumour initiation	Breast cancer	209,210
GH produced in ageing colon accumulates DNA damage	Tumour initiation	Colon cancer	143
Invasive tumour growth
GH increases miRNA-96, miRNA-182 and miRNA-183 cluster targeting BRMS1L	EMT induction	Breast cancer	186,211
GH induces CHOP expression via p38 MAPK activation	EMT induction	Breast cancer	212
GH supports tumour angiogenesis	Invasive growth	Breast cancer	120
GH drives migration, invasion and metastasis in tumour xenografts	Invasive growth and EMT induction	Breast cancer	213–215
GH deficiency reduces tumour growth rate in lit/lit mice	Tumour progression	Prostate cancer	216
GH increases migration, invasion, proliferation and MMP levels	Invasive growth	Prostate cancer	217
GH blockade reduces xenograft growth rate	Invasive growth	Colon cancer, meningioma	218,219
GH blockade reduces migration, invasion and markers of EMT	EMT induction	Melanoma, pancreatic cancer	180,181
GH production in lungs guides melanoma metastases in mice	Metastasis	Melanoma	187
GH inhibits tumour apoptosis via PI3K–AKT signalling	Invasive growth	Gastric cancer	220
Therapy resistance
GH increases ABC transporter expressions via JAK2-STAT5 and SRC signalling	Multidrug resistance	Melanoma	172
GH increases MITF-dependent melanogenesis and drug sequestration via JAK2–STAT5 and SRC	Multidrug resistance	Melanoma	154
GH increases ABCG2 levels via JAK2–STAT5	Docetaxel resistance	Breast cancer	174
GH increases PI3K–AKT–MAPK and JAK2 signalling	Ruxolitinib resistance	Breast cancer	145
GH reduces tumour apoptosis and increase proliferation	Doxorubicin resistance	Breast cancer	175
GH increases post-irradiation clonogenicity and reduces radiation-induced DNA damage	Radiation resistance	Colorectal cancer, breast cancer, endometrial cancer	171,221–223
GH induces FOS expression	Doxorubicin resistance	Breast cancer	224,225
GH suppress DNA damage and apoptosis	Mitomycin-C resistance	Breast cancer, endometrial cancer	226
GH activates ERK1/2 and PKC and suppresses caspase activation	Multidrug resistance	Endometrial cancer	227
GH reduces pro-apoptotic BAX and PPARγ via STAT5B activation	PPARγ ligand resistance	Colon cancer	228
GH reduces BAX, BAD, caspase 3, caspase 8 and caspase 9	Methylmethanosulfonate resistance	Lymphoma	229
GH increases ABCG2 and markers of cancer stem cells (NANOG, ALDH1, CD24 and CD44)	Increased stemness	Liver cancer, breast cancer, colon cancer	163,177,178,184,213
GH is a part of senescence-associated secretory phenotype	Therapy evasion and relapse	Colon cancer	31

ABC, ATP-binding cassette; bGH, bovine growth hormone; C3(1)/Tag-GHRKO mice, mice from a cross between Ghr-knockout (GHRKO) mice and C3(1)/Tag mice, where females develop spontaneous mammary tumours; DEN, diethylnitrosamine; DMBA, dimethylbenz[a]anthracene; EMT, epithelial-to-mesenchymal transition; GH, growth hormone; hTERT, human telomerase reverse transcriptase; miRNA, microRNA; MMP, matrix metalloproteinases; MNU, N-methyl-N-nitrosourea.