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SMC4
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<h2 id="structure-and-interactions">Structure and interactions</h2> <p>The primary 5 domain structure of <a href="/facts/SMC_protein/XhakqdLG">SMC proteins</a> is highly <a href="/facts/Conserved_sequence/YAxy2Xa2">conserved</a> among species. The basic structure of <a href="/facts/SMC_protein/XhakqdLG">SMC proteins</a> are characterized by a non-helical hinge group, separated by two anti-parallel α-helical <a href="/facts/Coiled_coil/U0YEzcB4">coiled-coil</a> domains, along with two Amino-terminal globular domains containing ATP hydrolytic sites, or nucleotide-binding motifs located at the <a href="/facts/C-terminus/ws4scHgT">C-terminus</a> and <a href="/facts/N-terminus/yKYpuaBJ">N-terminus</a> called the <a href="/facts/Walker_motifs/p49qD8FM">Walker A</a> and <a href="/facts/Walker_motifs/p49qD8FM">Walker B</a> motifs.<a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a> </p><p>In <a href="/facts/Eukaryote/SkwyPLMA">eukaryotes</a>, <a href="/facts/Dimerization/UFIw0Ua1">dimerization</a> is mediated by the self-folding of the non-helical hinge group on the SMC protein. Dimerization occurs at the non-helical hinge group of SMC-4, which then associates with the non-helical hinge group of SMC-2, creating a V-shaped <a href="/facts/Heterodimeric/c8LwFJPG">heterodimeric</a> structure. the holocomplex of condensin contains the SMC-4 and SMC-2 heterodimer subunits, along with 3 other non-SMC subunits, CAP-D2, CAP-G, and CAP-H.<a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a> </p><p>In the <a href="/facts/Condensin/fl4tzfpm">condensin holocomplex</a>, a protein subunit called kleisin joins the C-terminus and N-terminus <a href="/facts/ATPase/8aEJlNgl">ATPase</a> end domains of both SMC-4 and <a href="/facts/SMC2/4ygL6tUV">SMC-2</a> proteins. when the condensin holocomplex is bound with ATP at these end domains, the condensin will assume a "closed" conformation state.<a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a> SMC-4 is a <a href="/facts/Protein_dynamics/YGd6hP9U">dynamic</a> and flexible protein, allowing different domain components to occasionally interact with others. This is speculated to be involved in the mechanical ability of the complex when associated with chromosomes.<a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a> In budding yeast, these interactions may result in open "O" appearances, or collapsed B-shaped states as a result of its dynamic ability.<a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a> </p> <h2 id="clinical-significance">Clinical significance</h2> <p>The SMC-4 protein is associated with abnormal cell and tumor growth, and involved with migration and invasion. In general, the presence of over-expressed SMC-4 proteins is thought to be correlated with <a href="/facts/Carcinogenesis/PC8wc1Mf">carcinogenesis</a>.<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a> </p><p>It is found that an over-expression or down-regulation of the SMC-4 protein alters <a href="/facts/Transforming_growth_factor_beta/6bD65SWQ">TGFβ/Smad</a> signaling pathways in <a href="/facts/Glioma/I2gN3x11">glioma cells</a>. SMC-4-transduced glioma cells showed activation of the <a href="/facts/Transforming_growth_factor_beta/6bD65SWQ">TGFβ/Smad</a> signaling pathway which was not present in SMC-4 silenced glioma cells. This pathway was shown to be correlated with an "aggressive" behavioral phenotype in glioma cells. An over-expression of SMC-4 can induce a higher rate of proliferation, and ultimately increased invasive capability. A down-regulation of SMC-4 reduced this quality.<a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a> </p><p>The SMC-4 protein is involved with normal lung development however, adenocarcinoma lung tissue shows an over-expression of SMC-4. additionally, SMC-4 may act as independent prognostic factor for <a href="/facts/Carcinogenesis/PC8wc1Mf">carcinogenesis</a> and lung adenocarcinoma.<a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a> </p><p>Studies suggest that over-expression of the SMC-4 protein in human liver tissue may be correlated with progression of <a href="/facts/Hepatocellular_carcinoma/lE0P5CqE">hepatocellular carcinoma</a>.<a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a> </p> <h2 id="further-reading">Further reading</h2> <ul><li>Hirano T (February 2002). <a href="https://doi.org/10.1101%2Fgad.955102">"The ABCs of SMC proteins: two-armed ATPases for chromosome condensation, cohesion, and repair"</a>. <i>Genes & Development</i>. 16 (4): 399–414. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1101%2Fgad.955102">10.1101/gad.955102</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/11850403">11850403</a>.</li> <li>Ball AR, Yokomori K (2001). "The structural maintenance of chromosomes (SMC) family of proteins in mammals". <i>Chromosome Research</i>. 9 (2): 85–96. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1023%2FA%3A1009287518015">10.1023/A:1009287518015</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/11321372">11321372</a>. <a href="/facts/S2CID_(identifier)/ldJsHa2Y">S2CID</a> <a href="https://api.semanticscholar.org/CorpusID:23761326">23761326</a>.</li> <li>Ham MF, Takakuwa T, Rahadiani N, Tresnasari K, Nakajima H, Aozasa K (July 2007). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11158810">"Condensin mutations and abnormal chromosomal structures in pyothorax-associated lymphoma"</a>. <i>Cancer Science</i>. 98 (7): 1041–1047. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1111%2Fj.1349-7006.2007.00500.x">10.1111/j.1349-7006.2007.00500.x</a>. <a href="/facts/PMC_(identifier)/dX1zMt71">PMC</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11158810">11158810</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/17488335">17488335</a>. <a href="/facts/S2CID_(identifier)/ldJsHa2Y">S2CID</a> <a href="https://api.semanticscholar.org/CorpusID:25888221">25888221</a>.</li> <li>Nousiainen M, Silljé HH, Sauer G, Nigg EA, Körner R (April 2006). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1459365">"Phosphoproteome analysis of the human mitotic spindle"</a>. <i>Proceedings of the National Academy of Sciences of the United States of America</i>. 103 (14): 5391–5396. <a href="/facts/Bibcode_(identifier)/9HtdQSGB">Bibcode</a>:<a href="https://ui.adsabs.harvard.edu/abs/2006PNAS..103.5391N">2006PNAS..103.5391N</a>. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1073%2Fpnas.0507066103">10.1073/pnas.0507066103</a>. <a href="/facts/PMC_(identifier)/dX1zMt71">PMC</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1459365">1459365</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/16565220">16565220</a>.</li> <li>Geiman TM, Sankpal UT, Robertson AK, Chen Y, Mazumdar M, Heale JT, et al. (2004). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC419596">"Isolation and characterization of a novel DNA methyltransferase complex linking DNMT3B with components of the mitotic chromosome condensation machinery"</a>. <i>Nucleic Acids Research</i>. 32 (9): 2716–2729. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1093%2Fnar%2Fgkh589">10.1093/nar/gkh589</a>. <a href="/facts/PMC_(identifier)/dX1zMt71">PMC</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC419596">419596</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/15148359">15148359</a>.</li> <li>Wiemann S, Weil B, Wellenreuther R, Gassenhuber J, Glassl S, Ansorge W, et al. (March 2001). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC311072">"Toward a catalog of human genes and proteins: sequencing and analysis of 500 novel complete protein coding human cDNAs"</a>. <i>Genome Research</i>. 11 (3): 422–435. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1101%2Fgr.GR1547R">10.1101/gr.GR1547R</a>. <a href="/facts/PMC_(identifier)/dX1zMt71">PMC</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC311072">311072</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/11230166">11230166</a>.</li> <li>Kimura K, Cuvier O, Hirano T (February 2001). <a href="https://doi.org/10.1074%2Fjbc.C000873200">"Chromosome condensation by a human condensin complex in Xenopus egg extracts"</a>. <i>The Journal of Biological Chemistry</i>. 276 (8): 5417–5420. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1074%2Fjbc.C000873200">10.1074/jbc.C000873200</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/11136719">11136719</a>.</li> <li>Schmiesing JA, Gregson HC, Zhou S, Yokomori K (September 2000). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC88774">"A human condensin complex containing hCAP-C-hCAP-E and CNAP1, a homolog of Xenopus XCAP-D2, colocalizes with phosphorylated histone H3 during the early stage of mitotic chromosome condensation"</a>. <i>Molecular and Cellular Biology</i>. 20 (18): 6996–7006. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1128%2FMCB.20.18.6996-7006.2000">10.1128/MCB.20.18.6996-7006.2000</a>. <a href="/facts/PMC_(identifier)/dX1zMt71">PMC</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC88774">88774</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/10958694">10958694</a>.</li> <li>Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". <i>Gene</i>. 200 (1–2): 149–156. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1016%2FS0378-1119%2897%2900411-3">10.1016/S0378-1119(97)00411-3</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/9373149">9373149</a>.</li> <li>Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". <i>Gene</i>. 138 (1–2): 171–174. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1016%2F0378-1119%2894%2990802-8">10.1016/0378-1119(94)90802-8</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/8125298">8125298</a>.</li></ul> <h2 id="external-links">External links</h2> <ul><li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&singleSearch=knownCanonical&position=SMC4"><i>SMC4</i></a> human gene location in the <a href="/facts/UCSC_Genome_Browser/kwumPyLb">UCSC Genome Browser</a>.</li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_type=knownGene&hgg_gene=SMC4"><i>SMC4</i></a> human gene details in the <a href="/facts/UCSC_Genome_Browser/kwumPyLb">UCSC Genome Browser</a>.</li> <li><a href="https://www.ebi.ac.uk/pdbe/pdbe-kb/proteins/Q9NTJ3">PDBe-KB</a> provides an overview of all the structure information available in the PDB for Human Structural maintenance of chromosomes protein 4 (SMC4)</li> <li><a href="https://www.ebi.ac.uk/pdbe/pdbe-kb/proteins/Q8CG47">PDBe-KB</a> provides an overview of all the structure information available in the PDB for Mouse Structural maintenance of chromosomes protein 4 (SMC4)</li></ul> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>"Entrez Gene: SMC4 structural maintenance of chromosomes 4". <a href="https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=10051" target="_blank">https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=10051</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>Nishiwaki T, Daigo Y, Kawasoe T, Nagasawa Y, Ishiguro H, Fujita M, et al. (Jun 1999). "Isolation and characterization of a human cDNA homologous to the Xenopus laevis XCAP-C gene belonging to the structural maintenance of chromosomes (SMC) family". Journal of Human Genetics. 44 (3): 197–202. doi:10.1007/s100380050142. PMID 10319587. <a href="https://doi.org/10.1007%2Fs100380050142" target="_blank">https://doi.org/10.1007%2Fs100380050142</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>Schmiesing JA, Ball AR, Gregson HC, Alderton JM, Zhou S, Yokomori K (October 1998). "Identification of two distinct human SMC protein complexes involved in mitotic chromosome dynamics". Proceedings of the National Academy of Sciences of the United States of America. 95 (22): 12906–12911. Bibcode:1998PNAS...9512906S. doi:10.1073/pnas.95.22.12906. PMC 23650. PMID 9789013. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC23650" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC23650</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li> <li id="fn:4"><p>Eeftens JM, Katan AJ, Kschonsak M, Hassler M, de Wilde L, Dief EM, et al. (March 2016). "Condensin Smc2-Smc4 Dimers Are Flexible and Dynamic". Cell Reports. 14 (8): 1813–1818. doi:10.1016/j.celrep.2016.01.063. PMC 4785793. PMID 26904946. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4785793" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4785793</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li> <li id="fn:5"><p>Zhang C, Kuang M, Li M, Feng L, Zhang K, Cheng S (September 2016). "SMC4, which is essentially involved in lung development, is associated with lung adenocarcinoma progression". Scientific Reports. 6 (1): 34508. Bibcode:2016NatSR...634508Z. doi:10.1038/srep34508. PMC 5043270. PMID 27687868. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5043270" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5043270</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></p></li> <li id="fn:6"><p>Eeftens JM, Katan AJ, Kschonsak M, Hassler M, de Wilde L, Dief EM, et al. (March 2016). "Condensin Smc2-Smc4 Dimers Are Flexible and Dynamic". Cell Reports. 14 (8): 1813–1818. doi:10.1016/j.celrep.2016.01.063. PMC 4785793. PMID 26904946. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4785793" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4785793</a> <a href="#fnref:6" class="footnote-back-ref">↩</a></p></li> <li id="fn:7"><p>Jiang L, Zhou J, Zhong D, Zhou Y, Zhang W, Wu W, et al. (March 2017). "Overexpression of SMC4 activates TGFβ/Smad signaling and promotes aggressive phenotype in glioma cells". Oncogenesis. 6 (3): e301. doi:10.1038/oncsis.2017.8. PMC 5533949. PMID 28287612. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5533949" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5533949</a> <a href="#fnref:7" class="footnote-back-ref">↩</a></p></li> <li id="fn:8"><p>Zhou B, Chen H, Wei D, Kuang Y, Zhao X, Li G, et al. (June 2014). "A novel miR-219-SMC4-JAK2/Stat3 regulatory pathway in human hepatocellular carcinoma". Journal of Experimental & Clinical Cancer Research. 33 (1): 55. doi:10.1186/1756-9966-33-55. PMC 4096530. PMID 24980149. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4096530" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4096530</a> <a href="#fnref:8" class="footnote-back-ref">↩</a></p></li> <li id="fn:9"><p>Zhang C, Kuang M, Li M, Feng L, Zhang K, Cheng S (September 2016). "SMC4, which is essentially involved in lung development, is associated with lung adenocarcinoma progression". Scientific Reports. 6 (1): 34508. Bibcode:2016NatSR...634508Z. doi:10.1038/srep34508. PMC 5043270. PMID 27687868. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5043270" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5043270</a> <a href="#fnref:9" class="footnote-back-ref">↩</a></p></li> <li id="fn:10"><p>Hirano T (February 2002). "The ABCs of SMC proteins: two-armed ATPases for chromosome condensation, cohesion, and repair". Genes & Development. 16 (4): 399–414. doi:10.1101/gad.955102. PMID 11850403. S2CID 45664625. <a href="https://doi.org/10.1101%2Fgad.955102" target="_blank">https://doi.org/10.1101%2Fgad.955102</a> <a href="#fnref:10" class="footnote-back-ref">↩</a></p></li> <li id="fn:11"><p>Zhang C, Kuang M, Li M, Feng L, Zhang K, Cheng S (September 2016). "SMC4, which is essentially involved in lung development, is associated with lung adenocarcinoma progression". Scientific Reports. 6 (1): 34508. Bibcode:2016NatSR...634508Z. doi:10.1038/srep34508. PMC 5043270. PMID 27687868. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5043270" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5043270</a> <a href="#fnref:11" class="footnote-back-ref">↩</a></p></li> <li id="fn:12"><p>Eeftens JM, Katan AJ, Kschonsak M, Hassler M, de Wilde L, Dief EM, et al. (March 2016). "Condensin Smc2-Smc4 Dimers Are Flexible and Dynamic". Cell Reports. 14 (8): 1813–1818. doi:10.1016/j.celrep.2016.01.063. PMC 4785793. PMID 26904946. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4785793" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4785793</a> <a href="#fnref:12" class="footnote-back-ref">↩</a></p></li> <li id="fn:13"><p>Eeftens JM, Katan AJ, Kschonsak M, Hassler M, de Wilde L, Dief EM, et al. (March 2016). "Condensin Smc2-Smc4 Dimers Are Flexible and Dynamic". Cell Reports. 14 (8): 1813–1818. doi:10.1016/j.celrep.2016.01.063. PMC 4785793. PMID 26904946. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4785793" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4785793</a> <a href="#fnref:13" class="footnote-back-ref">↩</a></p></li> <li id="fn:14"><p>Ryu JK, Katan AJ, van der Sluis EO, Wisse T, de Groot R, Haering CH, Dekker C (December 2020). "The condensin holocomplex cycles dynamically between open and collapsed states". Nature Structural & Molecular Biology. 27 (12): 1134–1141. doi:10.1038/s41594-020-0508-3. PMID 32989304. S2CID 222146992. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:14" class="footnote-back-ref">↩</a></p></li> <li id="fn:15"><p>Jiang L, Zhou J, Zhong D, Zhou Y, Zhang W, Wu W, et al. (March 2017). "Overexpression of SMC4 activates TGFβ/Smad signaling and promotes aggressive phenotype in glioma cells". Oncogenesis. 6 (3): e301. doi:10.1038/oncsis.2017.8. PMC 5533949. PMID 28287612. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5533949" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5533949</a> <a href="#fnref:15" class="footnote-back-ref">↩</a></p></li> <li id="fn:16"><p>Jiang L, Zhou J, Zhong D, Zhou Y, Zhang W, Wu W, et al. (March 2017). "Overexpression of SMC4 activates TGFβ/Smad signaling and promotes aggressive phenotype in glioma cells". Oncogenesis. 6 (3): e301. doi:10.1038/oncsis.2017.8. PMC 5533949. PMID 28287612. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5533949" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5533949</a> <a href="#fnref:16" class="footnote-back-ref">↩</a></p></li> <li id="fn:17"><p>Zhang C, Kuang M, Li M, Feng L, Zhang K, Cheng S (September 2016). "SMC4, which is essentially involved in lung development, is associated with lung adenocarcinoma progression". Scientific Reports. 6 (1): 34508. Bibcode:2016NatSR...634508Z. doi:10.1038/srep34508. PMC 5043270. PMID 27687868. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5043270" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5043270</a> <a href="#fnref:17" class="footnote-back-ref">↩</a></p></li> <li id="fn:18"><p>Zhou B, Chen H, Wei D, Kuang Y, Zhao X, Li G, et al. (June 2014). "A novel miR-219-SMC4-JAK2/Stat3 regulatory pathway in human hepatocellular carcinoma". Journal of Experimental & Clinical Cancer Research. 33 (1): 55. doi:10.1186/1756-9966-33-55. PMC 4096530. PMID 24980149. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4096530" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4096530</a> <a href="#fnref:18" class="footnote-back-ref">↩</a></p></li> </ol>