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Placenta-specific protein 1

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PLAC1
Identifiers
AliasesPLAC1, CT92, OOSP2L, placenta specific 1, OOSP2B, placenta enriched 1
External IDsOMIM: 300296; MGI: 1926287; HomoloGene: 11039; GeneCards: PLAC1; OMA:PLAC1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

10761

56096

Ensembl

ENSG00000170965

ENSMUSG00000061082

UniProt

Q9HBJ0

Q9JI83

RefSeq (mRNA)

NM_021796
NM_001316887
NM_001316888
NM_001316889

NM_019538
NM_001357802

RefSeq (protein)

NP_001303816
NP_001303817
NP_001303818
NP_068568

NP_062411
NP_001344731

Location (UCSC)Chr X: 134.57 – 134.76 MbChr X: 52.16 – 52.33 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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

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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.[5]

Phylogenetics

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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.[6] 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.[7]

Function

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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.[8][9] 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.[10] PLAC1 expression terminates at the onset of labor and PLAC1 mRNAs clear the peripheral maternal circulatory system soon after delivery.[11][12][13]

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.[6][14] Numerous human gestational issues have been associated with abnormal PLAC1 expression including intrauterine growth restriction (IUGR),[15][16][17] premature birth,[18][19] implantation failure,[20][21][22][23] and preeclampsia.[24][25][26][27][28][29][30] Several of these studies have sought to develop PLAC1 assays into diagnostic tools with mixed success.

Cancer

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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.[31] 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,[32][33][34] colon/colorectal cancers,[34][35][36] liver cancers,[37][38] pancreatic cancers,[39] lung cancers,[40] and breast cancers.[41][42][43][44][45][46] 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,[47][48] uterine cancer,[49] ovarian cancer[50][51] and cervical cancer[52] 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).[9] This regulatory relationship has since been shown to be central to Akt Serine/Threonine kinase 1-mediated cancer cell proliferation.[53] 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.[54] PLAC1 expression is suppressed by wild-type p53 but increases in the presence of mutated or absent p53.[51]

Immunotherapy

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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.[55] Using anti-PLAC1/drug conjugates they have shown that PLAC1-based immunotherapy is highly promising.[47][48]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000170965 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000061082 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Chen Y, Moradin A, Schlessinger D, Nagaraja R (November 2011). "RXRα and LXR activate two promoters in placenta- and tumor-specific expression of PLAC1". Placenta. 32 (11): 877–884. doi:10.1016/j.placenta.2011.08.011. PMC 3210379. PMID 21937108.
  6. ^ a b Jackman SM, Kong X, Fant ME (August 2012). "Plac1 (placenta-specific 1) is essential for normal placental and embryonic development". Molecular Reproduction and Development. 79 (8): 564–572. doi:10.1002/mrd.22062. PMC 4594876. PMID 22729990.
  7. ^ Devor EJ (2014). "Placenta-specific protein 1 is conserved throughout the Placentalia under purifying selection". TheScientificWorldJournal. 2014: 537356. doi:10.1155/2014/537356. PMC 4142310. PMID 25180201.
  8. ^ Chang WL, Wang H, Cui L, Peng NN, Fan X, Xue LQ, et al. (September 2016). "PLAC1 is involved in human trophoblast syncytialization". Reproductive Biology. 16 (3): 218–224. doi:10.1016/j.repbio.2016.07.001. PMID 27692364.
  9. ^ a b Massabbal E, Parveen S, Weisoly DL, Nelson DM, Smith SD, Fant M (July 2005). "PLAC1 expression increases during trophoblast differentiation: evidence for regulatory interactions with the fibroblast growth factor-7 (FGF-7) axis". Molecular Reproduction and Development. 71 (3): 299–304. doi:10.1002/mrd.20272. PMID 15803460.
  10. ^ Chang WL, Yang Q, Zhang H, Lin HY, Zhou Z, Lu X, et al. (October 2014). "Role of placenta-specific protein 1 in trophoblast invasion and migration". Reproduction. 148 (4): 343–352. doi:10.1530/REP-14-0052. PMID 24989904.
  11. ^ Fant M, Weisoly DL, Cocchia M, Huber R, Khan S, Lunt T, et al. (December 2002). "PLAC1, a trophoblast-specific gene, is expressed throughout pregnancy in the human placenta and modulated by keratinocyte growth factor". Molecular Reproduction and Development. 63 (4): 430–436. doi:10.1002/mrd.10200. PMID 12412044.
  12. ^ Rawn SM, Cross JC (2008). "The evolution, regulation, and function of placenta-specific genes". Annual Review of Cell and Developmental Biology. 24: 159–181. doi:10.1146/annurev.cellbio.24.110707.175418. PMID 18616428.
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  22. ^ Shi LY, Ma Y, Zhu GY, Liu JW, Zhou CX, Chen LJ, et al. (October 2018). "Placenta-specific 1 regulates oocyte meiosis and fertilization through furin". FASEB Journal. 32 (10): 5483–5494. doi:10.1096/fj.201700922RR. PMID 29723063.
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  25. ^ Purwosunu Y, Sekizawa A, Farina A, Wibowo N, Okazaki S, Nakamura M, et al. (August 2007). "Cell-free mRNA concentrations of CRH, PLAC1, and selectin-P are increased in the plasma of pregnant women with preeclampsia". Prenatal Diagnosis. 27 (8): 772–777. doi:10.1002/pd.1780. PMID 17554801.
  26. ^ Kodama M, Miyoshi H, Fujito N, Samura O, Kudo Y (April 2011). "Plasma mRNA concentrations of placenta-specific 1 (PLAC1) and pregnancy associated plasma protein A (PAPP-A) are higher in early-onset than late-onset pre-eclampsia". The Journal of Obstetrics and Gynaecology Research. 37 (4): 313–318. doi:10.1111/j.1447-0756.2010.01349.x. PMID 21392164.
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  30. ^ Levine L, Habertheuer A, Ram C, Korutla L, Schwartz N, Hu RW, et al. (April 2020). "Syncytiotrophoblast extracellular microvesicle profiles in maternal circulation for noninvasive diagnosis of preeclampsia". Scientific Reports. 10 (1): 6398. Bibcode:2020NatSR..10.6398L. doi:10.1038/s41598-020-62193-7. PMC 7156695. PMID 32286341.
  31. ^ Chen J, Pang XW, Liu FF, Dong XY, Wang HC, Wang S, et al. (April 2006). "[PLAC1/CP1 gene expression and autologous humoral immunity in gastric cancer patients]". Beijing da Xue Xue Bao. Yi Xue Ban = Journal of Peking University. Health Sciences. 38 (2): 124–127. PMID 16617350.
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  33. ^ Liu W, Zhai M, Wu Z, Qi Y, Wu Y, Dai C, et al. (June 2012). "Identification of a novel HLA-A2-restricted cytotoxic T lymphocyte epitope from cancer-testis antigen PLAC1 in breast cancer". Amino Acids. 42 (6): 2257–2265. doi:10.1007/s00726-011-0966-3. PMID 21710262.
  34. ^ a b Liu FF, Shen DH, Wang S, Ye YJ, Song QJ (December 2010). "[Expression of PLAC1/CP1 genes in primary colorectal carcinoma and its clinical significance]". Zhonghua Bing Li Xue Za Zhi = Chinese Journal of Pathology. 39 (12): 810–813. PMID 21215095.
  35. ^ Liu F, Zhang H, Shen D, Wang S, Ye Y, Chen H, et al. (March 2014). "Identification of two new HLA-A*0201-restricted cytotoxic T lymphocyte epitopes from colorectal carcinoma-associated antigen PLAC1/CP1". Journal of Gastroenterology. 49 (3): 419–426. doi:10.1007/s00535-013-0811-4. PMID 23604623.
  36. ^ Liu F, Shen D, Kang X, Zhang C, Song Q (November 2015). "New tumour antigen PLAC1/CP1, a potentially useful prognostic marker and immunotherapy target for gastric adenocarcinoma". Journal of Clinical Pathology. 68 (11): 913–916. doi:10.1136/jclinpath-2015-202978. PMID 26157147.
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  38. ^ Wu Y, Lin X, Di X, Chen Y, Zhao H, Wang X (January 2017). "Oncogenic function of Plac1 on the proliferation and metastasis in hepatocellular carcinoma cells". Oncology Reports. 37 (1): 465–473. doi:10.3892/or.2016.5272. PMC 6365708. PMID 27878289.
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Further reading

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