KISS1/KISS1R in Cancer: Friend or Foe?

Abstract

The KISS1 gene encodes KISS1, a protein that is rapidly processed in serum into smaller but biologically active peptides called kisspeptins (KPs). KISS1 and the KPs signal via the G-protein coupled receptor KISS1R. While KISS1 and KPs are recognized as potent positive regulators of the reproductive neuroendocrine axis in mammals, the first reported role for KISS1 was that of metastasis suppression in melanoma. Since then, it has become apparent that KISS1, KPs, and KISS1R regulate the development and progression of several cancers but interestingly, while these molecules act as suppressors of tumorigenesis and metastasis in many cancers, in breast and liver cancer they function as promoters. Thus, they join a small but growing number of molecules that exhibit dual roles in cancer highlighting the importance of studying cancer in context. Given their roles, KISS1, KPs and KISS1R represent important molecules in the development of novel therapies and/or as prognostic markers in treating cancer. However, getting to that point requires a detailed understanding of the relationship between these molecules and different cancers. The purpose of this review is therefore to highlight and discuss the clinical studies that have begun describing this relationship in varying cancer types including breast, liver, pancreatic, colorectal, bladder, and ovarian. An emerging theme from the reviewed studies is that the relationship between these molecules and a given cancer is complex and affected by many factors such as the micro-environment and steroid receptor status of the cancer cell. Our review and discussion of these important clinical studies should serve as a valuable resource in the successful development of future clinical studies.

Low KISS1 expression predicts poor prognosis for patients with colorectal cancer: A meta‐analysis

“…In addition to the classic prognostic factors, molecular expression patterns provide more predictive information for clinical outcomes of CRC patients . For example, KISS1 and KISS1R, a new pair of metastasis suppressors in cancers, have been associated with CRC prognosis; however, conflicting results have been reported . The present study demonstrated that low KISS1 expression indicated poorer overall survival in CRC patients.…”

“…For example, in colorectal, bladder and renal cell carcinoma, KISS1 expression was decreased, and this was associated with lower survival rates and increases in metastasis. At the same time, in breast cancer stem cells, KISS1/KISS1R expression was upregulated, appeared to promote tumour growth and metastasis, and was associated with poor outcome . As Kostakis et al have previously proposed, Kisspeptins might possess tumour promotion properties or they might be activated in advanced disease stages as a defensive response against metastasis.…”

“…It is common that one molecule is capable of playing dual roles, being both a suppressor and a promoter of tumorigenesis and metastasis . Guzman et al recently summarized and discussed the crucial evidence in support of the proposal that KISS1/KISS1R acted as both a promoter and a suppressor of cancers. This review concluded that the role of KISS1/KISS1R was dependent on the cancer context, including cancer type, cancer stage and the composition of the microenvironment.…”

“…KISS1 and its cognate receptor, KISS1R, are proposed as a novel pair of metastasis suppressors in numerous cancers . The KISS1 protein, which is encoded on chromosome region 1q32.1, was first discovered in non‐metastatic human melanoma cells .…”

“…The KISS1 protein, which is encoded on chromosome region 1q32.1, was first discovered in non‐metastatic human melanoma cells . This premature protein contains 145 amino acids and is subsequently cleaved into derivatives called Kisspeptins, including Kisspeptin 10, 13, 14 and 54 . Kisspeptin exerts its biological effect by binding KISS1R, a G protein‐coupled receptor.…”