kiss1-protein--human and Cell-Transformation--Neoplastic

Kisspeptins, the products of the KISS1 gene have tumor suppressing and antimetastatic properties. We aimed to study KISS1 and KISS1R expression in colorectal cancer. We analyzed KISS1 and KISS1R expression using immunohistochemistry and image analysis in normal and malignant tissue samples from 111 patients with colorectal adenocarcinoma. KISS1 expression was much higher in the normal than in the malignant colonic mucosa. Regarding malignant tissues, KISS1 levels were higher in larger tumors, in stage III and IV cancers, in cancers with lymph node metastasis and in tumors located in the distal part of the large intestine. Patients with greater KISS1 levels had worse prognosis. No KISS1R expression was detected in normal or malignant tissues or in liver metastases. KISS1 expression is reduced during the malignant transformation of the colonic mucosa. However, larger and advanced colorectal cancers express more KISS1, without reaching the former normal levels, and increased KISS1 levels are associated with worse prognosis. Finally, neither the normal nor the malignant colonic epithelial cells produce KISS1R.

Topics: Aged; Biomarkers, Tumor; Cell Transformation, Neoplastic; Colorectal Neoplasms; Female; Humans; Immunohistochemistry; Intestinal Mucosa; Kisspeptins; Liver Neoplasms; Lymphatic Metastasis; Male; Prognosis; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1

Kisspeptins, the products of the KISS1 gene, are involved in cancer invasion, migration, metastasis and angiogenesis, while they induce apoptosis in various cancers. Herein, we studied KISS1 expression in colorectal cancer. We analyzed KISS1 expression using immunohistochemistry and image analysis in normal and malignant tissue samples from 60 patients with colorectal adenocarcinoma. The results correlated with various clinicopathological parameters. The expression of KISS1 was much higher in normal than in malignant colonic mucosa. However, among malignant tissues, KISS1 expression was higher in larger tumors (>4 cm) than in smaller ones (≤4 cm) and in stages III and IV than in stages I and II. In addition, it was higher in patients with lymph node metastases. Moreover, KISS1 levels in the normal mucosa and their difference from those in the malignant mucosa were higher in the right part of the large intestine than in the left one. KISS1 expression is reduced during the malignant transformation of the colonic mucosa and there is a difference in the expression pattern between the right and the left part of the large intestine. However, larger and advanced colorectal tumors express higher KISS1 levels than smaller and localized ones.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Cell Transformation, Neoplastic; Colon; Colorectal Neoplasms; Female; Gene Expression; Humans; Intestinal Mucosa; Kisspeptins; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Tumor Burden

Based on the importance of early-life events in breast cancer risk, we have investigated the effects of high-fat diets on maturation, mammary gland development, and its susceptibility to transformation. Female Sprague-Dawley rats were fed a lowfat (LF), high corn oil (HCO), or high extra-virgin olive oil (HOO) diet from weaning and gavaged with 7,12-dimethylbenz[a]anthracene. Body weight and mass increased in the HCO group compared to the LF group. The vaginal opening was advanced in both high-fat groups, especially in the HCO group. This HCO group also had increased body weight around puberty, more corpora lutea at post-puberty, and tended to have higher kisspeptin levels in the hypothalamus. Both high-fat diets induced subtle modifications in the morphology of the mammary gland, with no changes on β-casein or hormone receptors expression in the gland. The HCO diet had a clearly stimulating effect of carcinogenesis, inducing the earliest appearance of tumors and the highest tumor incidence and yield, whereas the HOO diet seemed to have a weak enhancing effect, increasing tumor yield. Our data suggest a strong influence of the HCO diet in sexual maturation and mammary cancer risk, while rats fed the HOO diet were more similar to the controls.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Amino Acid Sequence; Analysis of Variance; Animals; Body Weight; Breast; Caseins; Cell Transformation, Neoplastic; Corn Oil; Dietary Fats; Estrogen Receptor alpha; Female; Gene Expression Regulation, Neoplastic; Kisspeptins; Mammary Neoplasms, Experimental; Molecular Sequence Data; Olive Oil; Ovary; Plant Oils; Proteins; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sexual Maturation

Activation of KISS1 receptor (KISS1R or GPR54) by its ligands (Kisspeptins) regulates a diverse function both in normal physiology and pathophysiology. In cancer, KISS1R has been implicated in tumor angiogenesis and metastasis, but a broader evaluation of KISS1R in tumorigenesis and tumor progression is yet to be conducted. In this study, we used mouse models of Kiss1r gene knockout and mouse mammary tumor virus-polyoma virus middle T antigen (MMTV-PyMT)-induced breast cancer to conduct such an evaluation. Kiss1r heterozygosity in MMTV-PyMT mice was sufficient to attenuate breast cancer initiation, growth, latency, multiplicity, and lung metastasis. To confirm these effects and assess possible contributions of endogenous ligands, we isolated primary tumor cells from PyMT/Kiss1r(+/+) and PyMT/Kiss1r(+/-) mice and compared their phenotypes by in vitro and in vivo assays. Kiss1r loss attenuated in vitro tumorigenic properties as well as tumor growth in vivo in immunocompromised NOD.SCID/NCr mice. Kiss1r activation in these cells, resulting from the addition of its ligand Kisspeptin-10, resulted in RhoA activation and RhoA-dependent gene expression through the Gαq-p63RhoGEF signaling pathway. Anchorage-independent growth was tightly linked to dose-dependent regulation of RhoA by Kiss1r. In support of these results, siRNA-mediated knockdown of KISS1R or inactivation of RhoA in human MCF10A breast epithelial cells overexpressing H-RasV12 was sufficient to reduce Ras-induced anchorage-independent growth. In summary, we concluded that Kiss1r attenuation was sufficient to delay breast tumor initiation, progression, and metastasis through inhibitory effects on the downstream Gαq-p63RhoGEF-RhoA signaling pathway.

Topics: Animals; Antigens, Polyomavirus Transforming; Breast; Cell Transformation, Neoplastic; Female; Gene Expression Regulation, Neoplastic; Haploinsufficiency; Humans; Kisspeptins; Lung Neoplasms; Male; Mammary Neoplasms, Animal; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, SCID; Mice, Transgenic; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1; rho GTP-Binding Proteins; rhoA GTP-Binding Protein

Topics: Carcinoma, Transitional Cell; Cell Line, Tumor; Cell Transformation, Neoplastic; Gene Expression Regulation, Neoplastic; Humans; Kisspeptins; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1; RNA, Messenger; Tumor Suppressor Proteins; Urinary Bladder Neoplasms