Analysis of Signal Transducer and Activator of Transcription 3 (Stat 3) Pathway in Multiple Myeloma
Open accessAbstract
The signal transducer and activator of transcription molecules (Stats) play key roles in cytokine-induced signal transduction. Recently, it was proposed that constitutively activated Stat 3 (Stat 3 phosphorylated) contributes to the pathogenesis of multiple myeloma (MM) by preventing apoptosis and inducing proliferation. The study aim was to investigate Stat 3 activation in a series of multiple myeloma (MM) cases and its effect on downstream targets such as the anti-apoptotic proteins Bcl-xL, Mcl-1, and Bcl-2, and the cell-cycle protein cyclin D1. Forty-eight cases of MM were analyzed. Immunohistochemistry was performed on paraffin sections using antibodies against cyclin D1, Bcl-2, Bcl-xL, Mcl-1, p21, Stat 3, and Stat 3 phosphorylated (P). Their specificity was corroborated by Western blot analysis using eight human MM cell lines as control. The proliferation rate was assessed with the antibody MiB1. In addition, the mRNA levels of cyclin D1 and Stat 3 were determined by quantitative real-time reverse transcriptase-polymerase chain reaction of paraffin-embedded microdissected tissue. Three different groups determined by the expression of Stat 3P and cyclin D1 (protein and mRNA) were identified: group 1, Stat 3-activated (23 cases, 48%). All cases revealed nuclear expression of Stat 3P. No elevation of Stat 3 mRNA was identified in any of the cases. Three cases in this group showed intermediate to low cyclin D1 protein and mRNA expression. Group 2 included 15 (31%) cases with cyclin D1 staining and lack of Stat 3P. All cases showed intermediate to high levels of cyclin D1 mRNA expression. Group 3 included 10 (21%) cases with no expression of either cyclin D1 or Stat 3P. High levels of anti-apoptotic proteins Bcl-xL and Mcl-1 were identified in 89% and 100% of all cases, respectively. In contrast to Bcl-xL and Mcl-1, the expression of Bcl-2 showed an inverse correlation with proliferation rate (P: 0.0003). No significant differences were found between the three groups in terms of proliferation rate or expression of anti-apoptotic proteins. However, cyclin D1+ cases were always well differentiated and were more likely to show a lymphoplasmocytoid differentiation (chi-square = 9.55). Overall, constitutive activation of Stat 3 was found in almost half (48%) of the investigated MM cases. However, this does not seem to have a major impact on the expression of anti-apoptotic proteins and proliferation. We showed that cyclin D1 overexpression and Stat 3 activation are, mutually exclusive events in MM (P = 0.0066). The universal expression of Mcl-1, independent of activated Stat 3, suggests that its expression is constitutive and that it might play an important role in the pathogenesis of MM.
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Heightened levels of STAT3 expression are linked to poor prognosis, significantly shorter PFS, and overall survival in MM patients.
“Studies have shown that heightened levels of STAT3 expression are linked to a poor prognosis, significantly shorter PFS, and overall survival in MM patients [105, 106].”
From Multiple myeloma: signaling pathways and targeted therapy (2024) · cites this paper as [105]
In “Correlation between Activated Stat3 and Cyclin D1 Expression with Clinicopathological Characteristics and Outcome” (page unavailable), the paper reports no significant difference in overall survival between the STAT3-activated group and the comparison groups, contrary to the claimed shorter survival. The passages do not report a progression-free survival comparison. (LLM, conf=0.88)
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“For this purpose, we have chosen STAT3 and cyclin D1 proteins as targets because the expression of these proteins is associated with lymphomagenesis and cancer progression [15, 16], and they have different protein half-lives in the cells [16–18].”
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GP130 activation induces myeloma and collaborates with MYC
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Self-citationNovel STAT binding elements mediate IL-6 regulation of MMP-1 and MMP-3
Cutler, S. J., Doecke, J. D., Ghazawi, I., Yang, J., Griffiths, L. R., Spring, K. J., Ralph, S. J., & Mellick, A. S. (2017) · Scientific Reports · doi:10.1038/s41598-017-08581-y · Cited by 35 · see citing works
Graf, D., Kohlmann, C., Haselow, K., Gehrmann, T., Bode, J. G., & Häussinger, D. (2006) · Hepatology · doi:10.1002/hep.21368 · Cited by 32 · see citing works
IL-6 polymorphism in non-small cell lung cancer: a prognostic value?
Gomes, M. P., Coelho, A., Araújo, A., Azevedo, A. S., Teixeira, A. L., Catarino, R., & Medeiros, R. (2015) · Tumor Biology · doi:10.1007/s13277-014-3006-6 · Cited by 32 · see citing works
“On the other hand, by activating STAT3, it promotes the upregulated expression of cyclins D1, D2, B1, and MYC, as well as downregulates the expression of cdk inhibitor p21, thereby promoting the entry into the cell cycle [39–42].”
BackgroundDawson, M. A., Opat, S., Taouk, Y., Donovan, M., Zammit, M., Monaghan, K., Horvath, N., Roberts, A. W., Prince, H. M., Hertzberg, M., et al. (2009) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-08-1022 · Cited by 32 · see citing works
Khattar, N. H., Lele, S. M., & Kaetzel, C. S. (2005) · Journal of Biomedical Science · doi:10.1007/s11373-004-8185-5 · Cited by 31 · see citing works
Burger, R., Günther, A., Klausz, K., Staudinger, M., Peipp, M., Penas, E. M. M., Rose‐John, S., Wijdenes, J., & Gramatzki, M. (2016) · Haematologica · doi:10.3324/haematol.2016.145060 · Cited by 31 · see citing works
Bicyclic triterpenoid Iripallidal induces apoptosis and inhibits Akt/mTOR pathway in glioma cells
Koul, N., Sharma, V., Dixit, D., Ghosh, S., & Sen, E. (2010) · BMC Cancer · doi:10.1186/1471-2407-10-328 · Cited by 27 · see citing works
Ahsan, H., Aziz, M. H., & Ahmad, N. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.05.106 · Cited by 25 · see citing works
Emerging protein kinase inhibitors for the treatment of multiple myeloma
Lind, J., Czernilofsky, F., Vallet, S., & Podar, K. (2019) · Expert Opinion on Emerging Drugs · doi:10.1080/14728214.2019.1647165 · Cited by 24 · see citing works
Kim, J.-H., & Park, B. (2017) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2017.3122 · Cited by 23 · see citing works
“…active Stat3 is also important in the survival and proliferation of myeloma, as ~48% of mm patients have a constitutively active form of Stat3 (48). regarding the mechanisms of Stat3 inhibition, it was observed in the present study that triptolide inhibited il-6-induced and constitutive Stat3…”
Kinase inhibitors as potential agents in the treatment of multiple myeloma
Abramson, H. N. (2016) · Oncotarget · doi:10.18632/oncotarget.10745 · Cited by 23 · see citing works
“Lee JH, Kim C, Kim SH, Sethi G and Ahn KS. Farnesol inhibits tumor growth and enhances the anticancer effects of bortezomib in multiple myeloma xenograft mouse model through the modulation of STAT3 signaling pathway.”
BackgroundInfluentialBuettner, M. J., Heußinger, N., & Niedobitek, G. (2006) · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin · doi:10.1007/s00428-006-0294-2 · Cited by 22 · see citing works
“Moreover, STAT3 was implicated in the development of epithelial and lymphatic malignancies such as breast cancer [3], multiple myeloma [22], squamous cell carcinoma of head and neck (SCCHN) [26] and in the Epstein–Barr virus (EBV) associated tumours, nasopharyngeal carcinoma (NPC) and Hodgkin lymphoma (HL) [9, 16, 25].”
BackgroundNgo, B. T., Felthaus, J., Hein, M., Follo, M., Wider, D., Ihorst, G., Engelhardt, M. M., & Wäsch, R. (2010) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.3109/10428194.2010.496014 · Cited by 21 · see citing works
“As the CCND1 protein has a short half-life due to posttranslational regulation by ubiquitination and proteasomal degradation [1,9], this might provide a therapeutic rationale for blocking CCND1 degradation using a 26S proteasome inhibitor, thus amplifying antitumorigenic activity [2,10].”
BackgroundBrill, T., Kübler, H. R., van Randenborgh, H., Fend, F., Pohla, H., Breul, J., Härtung, R., Paul, R., Schendel, D. J., & Gänsbacher, B. (2007) · The Journal of Gene Medicine · doi:10.1002/jgm.1051 · Cited by 21 · see citing works
“Immunostaining using heat-induced antigen retrieval was performed as described previously on an automated immunostainer (Ventana Benchmark, Ventana) according to standard protocols [86].”
MethodSelf-citationKreps, L. M., & Addison, C. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22062911 · Cited by 20 · see citing works
Szymanski, P. T., Kuppast, B., Ahmed, S. A., Khalifa, S. I., & Fahmy, H. T. Y. (2011) · Marine Drugs · doi:10.3390/md10010001 · Cited by 19 · see citing works
Wang, L., Zhang, X., Farrar, W. L., & Yang, X. (2004) · PubMed · Cited by 19 · see citing works
Brown, R. D., Yang, S. S., Weatherburn, C., Gibson, J., Ho, P. J., Suen, H., Hart, D. N. J., & Joshua, D. E. (2014) · Leukemia · doi:10.1038/leu.2014.204 · Cited by 18 · see citing works
Characterization of MENX‐associated pituitary tumours
Marinoni, I., Lee, M., Mountford, S., Perren, A. A., Bravi, I., Jennen, L., Feuchtinger, A., Drouin, J., Roncaroli, F., & Pellegata, N. S. (2012) · Neuropathology and Applied Neurobiology · doi:10.1111/j.1365-2990.2012.01278.x · Cited by 18 · see citing works
Hayashi, T., Shibata, M., Oe, S., Miyagawa, K., Honma, Y., & Harada, M. (2020) · PLoS ONE · doi:10.1371/journal.pone.0244370 · Cited by 16 · see citing works
“Activated STAT3 mediates the expression of genes involved with cell proliferation and promotes the cell cycle via expression of cyclins D1, D2 and D3 and c-Myc [37,38].”
BackgroundIGF‐1 stimulated upregulation of cyclin D1 is mediated via STAT5 signaling pathway in neuronal cells
Kalita, A., Gupta, S., Singh, P., Surolia, A., & Banerjee, K. (2013) · IUBMB Life · doi:10.1002/iub.1152 · Cited by 16 · see citing works
Pellegata, N. S., Quintanilla‐Martinez, L., Keller, G., Liyanarachchi, S., Höfler, H., Atkinson, M. J., & Fend, F. (2007) · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin · doi:10.1007/s00428-007-0431-6 · Cited by 16 · see citing works
“Sections were cut at 3 μM and stained immunohistochemically using an automated immunostainer (Ventana Medical System, Tucson, AZ, USA) according to previously published procedures [37].”
MethodSelf-citationCaspase-mediated cleavage of the signal-transducing IL-6 receptor subunit gp130
Graf, D., Haselow, K., Münks, I., Bode, J. G., & Häussinger, D. (2008) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2008.06.009 · Cited by 14 · see citing works
Estrogenic or antiestrogenic therapies for multiple myeloma?
Sola, B., & Renoir, J. (2007) · Molecular Cancer · doi:10.1186/1476-4598-6-59 · Cited by 15 · see citing works
“Importantly, also, SERMs could interfere with survival pathways known to be constitutively activated in MM such as Janus Kinase (JaK)/STAT3 [40,41], NF-κB (nuclear factor-κB) [42,43] and Ras/MAPK (mitogen-activated protein kinase) [44,45].”
Miederer, M., Molatore, S., Marinoni, I., Perren, A. A., Spitzweg, C., Reder, S., Wester, H., Buck, A. K., Schwaiger, M., & Pellegata, N. S. (2011) · International Journal of Molecular Imaging · doi:10.1155/2011/175352 · Cited by 14 · see citing works
“Immunohistochemistry was performed on an automated immunostainer (Ventana Medical systems, Illkirch, France) according to the manufacturer’s protocols with minor modifications, as described elsewhere [10].”
MethodCAMKIIγ is a targetable driver of multiple myeloma through CaMKIIγ/ Stat3 axis
Yang, L., Wu, B., Wu, Z., Xu, Y., Wang, P., Li, M., Xu, R., & Liang, Y. (2020) · Aging · doi:10.18632/aging.103490 · Cited by 13 · see citing works
Pathogenic signaling in multiple myeloma
Bolomsky, A., & Young, R. M. (2022) · Seminars in Oncology · doi:10.1053/j.seminoncol.2022.01.005 · Cited by 13 · see citing works
Slotta‐Huspenina, J., Koch, I., Richter, M., Bink, K., Kremer, M., Specht, K., Krugmann, J., Quintanilla‐Martínez, L., & Fend, F. (2007) · Leukemia Research · doi:10.1016/j.leukres.2007.05.021 · Cited by 12 · see citing works
Self-citationLi, M., Chen, C., Wang, Q., Jiang, X., Tan, L., Huang, Y., Zhang, Y., & Zhang, Z. (2021) · Cancer Cell International · doi:10.1186/s12935-021-02375-z · Cited by 10 · see citing works
“In recent researches about MM therapies, STAT3 was found highly expressed in many CD138 positive cells isolated from primary MM patients, and its expression is often associated with MM pathogenesis and its chemoresistance to most of the clinical therapies [4, 5].”
BackgroundBcl-xl Expression in Multiple Myeloma
Peeters, S. D. P. W. M., Hovenga, S., Rosati, S., & Vellenga, E. (2005) · Medical Oncology · doi:10.1385/mo:22:2:183 · Cited by 9 · see citing works
Acromegaly due to a Macroinvasive Plurihormonal Pituitary Adenoma and a Rectal Carcinoid Tumor
Chin, S. O., Hwang, J.-K., Rhee, S. Y., Chon, S., Oh, S., Lee, M., Pellegata, N. S., & Kim, S.-W. (2015) · Endocrinology and Metabolism · doi:10.3803/enm.2015.30.3.389 · Cited by 8 · see citing works
Chae, H., Kim, Y., & Chin, Y. (2017) · Natural Product Sciences · doi:10.20307/nps.2017.23.1.1 · Cited by 8 · see citing works
Kannaiyan, R., Surana, R., Myoung, E., Ramachandran, L., Sethi, G., & Kumar, A. P. (2012) · InTech eBooks · doi:10.5772/30444 · Cited by 7 · see citing works
“Knock down of Bcl-2 can augment dexamethasone induced apoptosis [139], but again, the importance of STAT3 in regulating the anti-apoptotic proteins and thereby the survival of myeloma cells remains controversial in the light of a lack of correlation between the constitutive expression of STAT3 and the anti-apoptotic p…”
BackgroundLiu, N., Xie, Z., Li, H., & Wang, L. (2024) · Oncology Letters · doi:10.3892/ol.2024.14391 · Cited by 6 · see citing works
Bioactive Compounds from Herbal Medicine Targeting Multiple Myeloma
Cotoraci, C. A., Ciceu, A., Sasu, A., Miuţescu, E., & Hermenean, A. O. (2021) · Applied Sciences · doi:10.3390/app11104451 · Cited by 5 · see citing works
Huang, Y.-H., Almowaled, M., Li, J., Venner, C. P., Sandhu, I., Peters, A., Lavasanifar, A., & Lai, R. L. (2021) · Current Issues in Molecular Biology · doi:10.3390/cimb43010026 · Cited by 5 · see citing works
“The third study reported that around 50% of 48 cases showed pSTAT3 (Y705) positivity in CD138+ MM cells by immunohistochemical analysis [17].”
BackgroundZou, Z., Yin, Y., Lin, J., Hsu, L.-C. J., Brandon, V. L., Yang, F., Jove, R., Jandial, R., Li, G., & Chen, M. Y. (2015) · Journal of neurosurgery · doi:10.3171/2015.3.jns132040 · Cited by 5 · see citing works
Sikka, S., Shanmugam, M. K., Kannaiyan, R., Surana, R., Shin, E. M., Kumar, A. P., Sethi, G., & Ahn, K. S. (2013) · Phytochemistry Reviews · doi:10.1007/s11101-013-9287-3 · Cited by 4 · see citing works
Modulation of Apoptosis Pathways in the Biology and Treatment of Multiple Myeloma
Bansal, R., Rakshit, S., Han, W., & Kumar, S. K. (2021) · touchREVIEWS in Oncology & Haematology · doi:10.17925/ohr.2021.17.1.48 · Cited by 2 · see citing works
“Several autocrine and paracrine loops (particularly IL-6) activate the Janus family of kinase (JAK) by binding to gp130, which induces downstream phosphorylation and dimerization of the cytoplasmic signal transducer, and activator of transcription (STAT)3.50,51 This dimer translocates to the nucleus and activates tran…”
BackgroundInfluentialMolekulare Pathologie von Plasmazellneoplasien
Fend, F. (2010) · Der Pathologe · doi:10.1007/s00292-010-1375-1 · Cited by 2 · see citing works
Self-citationA Brief Review on Dual Target of PARP1 and STAT3 for Cancer Therapy: A Novel Perception
Lakshmanan, K., Byran, G., & Mohammed, M. (2020) · Current Enzyme Inhibition · doi:10.2174/1573408016666200316114209 · Cited by 2 · see citing works
Differential Regulation of Cytochrome C Release in Dexamethasone-Resistant 7TD1 Cells
Gangavarapu, K. J., Bhushan, A., Lai, J. C. K., & Daniels, C. K. (2013) · Journal of Cancer Therapy · doi:10.4236/jct.2013.44095 · Cited by 1 · see citing works
Clinical and biological aspects of Multiple Myeloma
Hovenga, S. (2007) · University of Groningen research database (University of Groningen / Centre for Information Technology)
Miederer, M., Molatore, S., Marinoni, I., Perren, A. A., Spitzweg, C., Reder, S., & Pellegata, N. S. (2011)
Mathematisch-naturwissenschaftlichen Fakultät, I. (2009)
Investigation of the mechanisms of estrogen receptor activation by phosphorylation
Halliday, A. C. (2009) · Spiral (Imperial College London) · doi:10.25560/4348
“AIB1 is capable of shuttling between the nucleus and the cytoplasm and the phosphorylation status of AIB1 has also been linked to an increased dwell-time in the nucleus (Qutob et al., 2002; Wu et al., 2002a).”
BackgroundPeriplocin targets STAT3 to suppress MYC expression and inhibit multiple myeloma cell proliferation
Wei, R.-F., Chen, J., Lai, S.-P., Chen, Z.-A., Zhou, Y.-Y., Liao, Y.-P., & Chen, Y. (2026) · Journal of Chinese Integrative Medicine · doi:10.1016/j.joim.2026.07.002
JAK Kinases in Leukemias, Lymphomas, and Multiple Myeloma
Burger, R., & Gramatzki, M. (2006) · Humana Press eBooks · doi:10.1385/1-59259-962-1:115 · Cited by 1 · see citing works
- Authors
- Quintanilla-Martinez, L., Kremer, M., Specht, K., Calzada-Wack, J., Nathrath, M., Schaich, R., Höfler, H., & Fend, F.
- Affiliations
- Helmholtz Munich (DE)
- Technical University of Munich (DE)
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2003-05
- Volume
- 162
- Issue
- 5
- Pages
- 1449-1461
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC1851203
- OpenAlex
- W1946894092
- Semantic Scholar
- 58dd102b9ab3a665e9a77d87944f5156a7b36e30
- Cited by
- 93
- References
- 35
- Citations by year
- 2026: 1 · 2024: 2 · 2022: 1 · 2021: 6 · 2020: 3 · 2019: 3 · 2018: 2 · 2017: 3 · 2016: 2 · 2015: 3 · 2014: 2 · 2013: 8 · 2012: 5
- FWCI
- 3.48
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- American Journal Of Pathology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Site cant be reached (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Topics
- Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Keywords
- STAT3 phosphorylation, multiple myeloma, STAT3 signaling, cyclin D1, Bcl-xL, Mcl-1, Bcl-2, apoptosis, cell proliferation, prognostic factors, p21, cell cycle regulation, transcription factor activation, gene expression profiling, immunohistochemistry
- MeSH terms
- Aged, Base Sequence, DNA-Binding Proteins, Female, Humans, Immunohistochemistry, Male, Middle Aged, Multiple Myeloma, Neoplasm Staging, Phosphorylation, Signal Transduction, Trans-Activators, Interleukin-6, Gene Expression Regulation, Neoplastic, Apoptosis, DNA Primers, Cyclin D1, Reverse Transcriptase Polymerase Chain Reaction, STAT3 Transcription Factor
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