In 1996, and its following 20 years, kisspeptin1 (KiSS1, full-length human KiSS1, a 145 amino acid protein) and KiSS1-derived peptides (KiSS 54,14, 13, 10) and their receptor calling G protein coupled receptor 54 (GPR54, called KiSS1R) system are initially found to possess a strong antimetastatic ability (called a metastasis suppressor).1 The largely antimetastatic role is found in various kinds of cancers, such as melanoma, ovarian, bladder, endometrial cancers, and others.1 However, reports have shown that KiSS/KiSS1R system involved in cancers is not only limited on antimetastatic process but also plays a promotion of cancer metastases or dissemination, of which depending on the type of cancers. The diverse actions of either anti- or prometastatic effects of cancers remain unclear, although there are several pathways, including autocrine, paracrine, and endocrine pathway as well as epigenetic control of the KiSS/KiSS1R system reported to be involved in the reciprocal results.2 Furthermore, a reciprocal communication between KiSS/KiSS1R of the tumor-surrounding cells in the tumor microenvironment (TEM) is also a reason.3,4 Moreover, it is also possible that an existence of other unknown mediators modifies KiSS/KiSS1R system in cancers.1 All are too complex, with resultant research for KiSS/KiSS1R system hampering the progress in gaining mechanistic insights on the KiSS/KiSS1R axis in cancers.
Unlike to the uncertain role of KiSS/KiSS1R on cancers, the progress on the role of KiSS/KiSS1R system in reproduction has been rapidly developed since 2003, after an identification of KiSS/KiSS1R inactivating/hyperactivating mutations causing hypogonadotropic hypogonadism/precocious puberty,5,6 in turn drawing a bright picture in the endocrine and local control of reproduction, which includes an initiation of puberty, timing control of puberty, and regulation of fertility in adulthood.7 Within the central neurological system (brain), KiSS/KiSS1R system is a positive modulator of gonadotropin-releasing hormone (GnRH) secreting neurons located in the arcuate nucleus (ARC) thus affecting gonadotropin (follicular stimulating hormone [FSH] and luteinizing hormone [LH]) secretion, sex maturation, and sex hormone biosynthesis (called as hypothalamic-pituitary-gonadal [HPG] axis), and mediating sex hormone positive and negative feedback mechanisms by gonadal steroids.5–7 Furthermore, the KiSS/KiSS1R system also represents a fundamental “sensor” for environmental cues like energy availability and thus linking reproductive ability to metabolism with epigenetic mechanism.6
Besides in brain, KiSS/KiSS1R system is widely distributed in peripheral tissues, including gonads, adipose tissue, liver, placenta, pancreas and small bowel, contributing to a wider spectrum of action related to reproduction, fertility, body weight, and energy homeostasis, and cardiovascular system.7–11 Based on above-mentioned observation, we are happy to introduce the recent article entitled “Role of the kisspeptin/KISS1 receptor system in the testicular development of mice” published in this February issue of the Journal of the Chinese Medical Association.12
In the current article, Dr. Chiang et al’s12 group carried out an in vivo observation of cellular pattern of KiSS/KiSS1R in testis tissue of mice model and found that KiSS was identified clearly in the cytoplasm of Leydig cells located adjacent to the seminiferous tubules and KiSS1R was observed in the seminiferous tubules by immunohistochemical staining. Furthermore, gene expression of KiSS was detected in the fourth postnatal week (initiation of maturation of mice), but gene expression of KiSS1R has been already existed immediately when these mice were born with at least 4 weeks of lag.12 A further in vitro study, the expression of KiSS in the testis was related to the maturation process, which was responsible to LH stimulation.12 Further dissection of this observation, the authors found that KiSS secretion in Leydig cells was mediated through LH-associated cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) pathway.12 Taken together, the authors suggested that KiSS- and development-related factors have synergistic effects on spermatogenesis.12 This finding further draws the important role of KiSS/KiSS1R system in male reproduction and some are worthy of discussion.
Classically, spermatogenesis is tightly orchestrated step by step leading to the production of male gametes within the testis by coordination of mitotic, meiotic, and maturation events, mediated by endocrine, paracrine, autocrine, and epigenetic effect.7 Based on the facts showing (1) peripheral KiSS administration accelerates spermatogenesis; (2) over-activating mutations in KiSS/KiSS1R signaling result in precocious puberty; (3) silencing mutations in KiSS/KiSS1R system lead to hypogonadotropic hypogonadism; (4) in-activating mutations in KiSS/KiSS1R system decrease the testosterone biosynthesis, which cannot be reversed by gonadotropin stimulation; (5) the conditional KiSS/KiSS1R system reactivation in the GnRH secreting neuron in total knockout of KiSS1R−/− (KiSS1R KO) mice cannot restore the normal spermatogenesis; and (6) subcutaneous testosterone supplementation for 6 weeks restores plasma and intratesticular testosterone levels, elicits testicular descent, and induces complete spermatogenesis from spermatocytes to elongated spermatids in the testis, resulting in an increase in epididymal sperm number in testosterone-supplemented KiSS−/− (KiSS KO) male mice but those KiSS KO male mice do not ejaculate or form copulatory plugs, all indicate that normal function of KiSS/KiSS1R system within the testis is critical for steroid genesis and spermatogenesis.7,13,14 As shown by authors,12 the persistent expression of KiSS1R in the interstitial cells (Leydig cells) was found when male mice were born (0 postnatal week) and the expression of KiSS occurred when sexual maturation of male mice was induced by LH stimulation (the fourth postnatal week), indicating that the sexual maturation of male mice indeed requests the cooperation of central and peripheral function. However, the LH secretion is controlled by GnRH, which needs the KiSS/KiSS1R system in brain, suggesting that it is uncertain the role of KiSS on the impact of the next upward rung in the pubertal cascade and how that impacts initiation and maintenance of spermatogenesis and male fertility.
There is no doubt that the intratesticular role of KiSS/KiSS1R system is far away to be elucidated, although KiSS/KiSS1R system can locally modulate different aspect of male reproduction, from spermatogenesis progression to the acquisition of sperm maturation and normal sperm functions, with effects being dependent on species, dose or spice form of KiSS, and extra administration of KiSS by different routes and durations.7 All factors are involved in the balance of ARC-HPG axis, leading to impairment or enhancement of steroid production and spermatogenesis.
Additionally, the fundamental limitation of the current Dr. Chiang et al’s study12 is the underestimation of role secondary to paracrine, and endocrine effect in the testis development. The authors did not evaluate the connection, relation, or communication between targeted cells (Leydig cells or germ cells) and their surrounding cells within the testis structure. In fact, extra KiSS administration resulting in hyperstimulation and subsequent downregulation of HPG axis in mammals contributes to end points of testis degeneration.7 Therefore, most studies used the in vitro cell treatment model to investigate the role of KiSS/KiSS1R system in reproduction function, a situation in which the precise effects of paracrine and endocrine interaction between somatic (Leydig cells) and germ cells (spermatogenesis) are totally lost.7
In conclusion, issue about the fertility and enhanced fecundability ability becomes more and more urgent because of aged population and dramatical change of the environment, such as a lots of toxins or pollutions in modern society.15,16 The mysteries of KiSS/KiSS1R system either in reproduction or in oncology may need more efforts to dissect and we believe that the KiSS/KiSS1R system may become one of the most promising targeted sites in dealing with various kinds of global health problems in the near future.
This article was supported by grants from the Ministry of Science and Technology, Executive Yuan, Taiwan (MOST 109-2314-B-075B-014-MY2 and MOST 109-2314-B-075-056), and Taipei Veterans General Hospital (V110C-082, and VGH109E-005-5).
The authors appreciate the support from Female Cancer Foundation, Taipei, Taiwan.
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