PLAC1

Placenta-specific protein 1 is a small (212 amino acid), secreted cell surface protein encoded on the X-chromosome by the PLAC1 gene. Since its discovery in 1999, PLAC1 has been found to play a role in placental development and maintenance, several gestational disorders including preeclampsia, fetal development and a large number of cancers.

Genomics
PLAC1 is located on the long arm of the X-chromosome at Xq26.3. The gene consists of six Exons spanning nearly 200Kb (GRCh38/hgs38; X:134,565,838 - 134,764,322). The entire coding sequence plus the 3’ UTR and part of the 5’ UTR constitute Exon 6 while Exons 1 – 5 contain variously spliced elements of the rest of the 5’UTR including two independently regulated promoters.

These two promoters, termed P1 (or distal) and P2 (or proximal) are located in Exons 1 and 4 respectively. They have been shown to produce transcripts simultaneously though P1 transcription predominates in cancers and P2 transcription predominates in placentae[7].

Phylogenetics
From its initial description, the consensus is that PLAC1 is highly conserved and that this conservation reflects an important role in the establishment and maintenance of the placenta[8]. A detailed study of the PLAC1 gene and protein among 54 placental mammal species representing twelve crown orders confirms a high level of conservation under the control of strict purifying selection[9]. Further, comparative genomic sequences from two marsupials, the opossum (Mondelphis domestica) and the wallaby (Macropus eugenii), a monotreme, the platypus (Ornithorhynchus anatinus), two avians, the chicken (Gallus gallus) and the finch (Taeniopygia guttata), and two fish, the zebrafish (Danio rerio) and the stickleback (Gasterosteus arculeatus)  spanning the synthenic X-chromosome region from PHD finger protein 6 (PHD6) through Factor 9 (F9) were screened for any sequences similar to PLAC1. The screen showed that PLAC1 appeared in the animal genome concurrent with the emergence of the Placentalia some 165,000,000 years ago[10].

Function
Discovery of PLAC1 resulted from an examination of the region around the human hypoxanthine ribosyltransferase 1 (HPRT) gene aimed at determining whether or not a placenta-specific protein was encoded there. This question was raised because the region was believed to be involved in both placental and fetal pathologies. Once identified, PLAC1 and its mouse ortholog Plac1 were found to be expressed throughout gestation[11,12]. It was quickly established that PLAC1 expression is specific to trophoblast cells and that it is a critical element in establishing and maintaining a normal placenta. Expression was further localised to the apical region of the syncytiotrophoblast, the leading, invasive part of the developing embryo[13]. PLAC1 expression terminates at the onset of labor and PLAC1 mRNAs clear the peripheral maternal circulatory system soon after delivery[14-16].

Recognition that PLAC1 plays an important role in first establishing the placenta and, subsequently, in maintaining it throughout gestation leads to the idea that PLAC1 may play a role in gestational issues from infertility to premature birth. An important contribution to this idea is the observation that a Plac1 knockout mouse model exhibited both placentomegaly in the dams and growth restriction in the pups[8,17]. Numerous human gestational issues have been associated with abnormal PLAC1 expression including intrauterine growth restriction (IUGR)[18-20], premature birth[21,22], implantation failure[23–26], and preeclampsia[27-33]. Several of these studies have sought to develop PLAC1 assays into diagnostic tools with mixed success.

Cancer
While it has been clearly established that PLAC1 is truly placenta-specific, almost from the outset it was also clear that PLAC1 is co-opted in human cancers. The first evidence that PLAC1 is co-opted in cancer was published in 2006[34]. Since then, PLAC1 expression has been demonstrated in more than a dozen human cancers and in at least one hundred human cancer cell lines. Among the cancers in which PLAC1 expression is evident are gastric cancers[35-37], colon/colorectal cancers[37-39], liver cancers[40,41], pancreatic cancers[42], lung cancers[43], and breast cancers[44-49]. In nearly all cases, PLAC1 expression is associated with poor clinical outcomes. Nowhere is this more true than in cancers of the male and female reproductive tract. That is, prostate cancer[50,51], uterine cancer[52], ovarian cancer[53,54] and cervical cancer[55] all have demonstrated a positive correlation between PLAC1 expression and prognosis.

In 2005, PLAC1 expression in differentiating fibroblasts was shown to be regulated by fibroblast growth factor 7 (FGF7)[56]. This regulatory relationship has since been shown to be central to Akt Serine/Threonine kinase 1-mediated cancer cell proliferation[57]. PLAC1 forms a cell surface complex with FGF7 and the FGFR2IIIb receptor which then activates a cascade leading to Akt phosphorylation. Expression of PLAC1is, in turn, partially determined by the p53 tumor suppressor[58]. PLAC1 expression is suppressed by wild-type p53 but increases in the presence of mutated or absent p53[54].

Immunotherapy
PLAC1 is classified as a “cancer-testis antigen” as it is preferentially expressed in trophoblasts and tumors. In addition to results associating PLAC1 expression with risk of various cancers as well as with prognosis, the ability of PLAC1 to elicit an immune response suggests that its specificity could be harnessed therapeutically. One group in particular is pioneering the potential[59]. Using anti-PLAC1/drug conjugates they have shown that PLAC1-based immunotherapy is highly promising[50, 51].