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Cited by 74Cellular transport and secretionMechanisms of cancer metastasisExtracellular vesicles in disease

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Secretory RAB GTPase 3C modulates IL6-STAT3 pathway to promote colon cancer metastasis and is associated with poor prognosis

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Chang, Yu-Chan, Su, Chia-Yi, Chen, Ming-Huang, Chen, Wei-Shone, Chen, Chi-Long, Hsiao, Michael·2017·Molecular Cancer
DOI 10.1186/s12943-017-0687-7PMC PMC5547507
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Abstract

BACKGROUND: RAB GTPases are important in the regulation of membrane trafficking and cell movement. Recently, exocytic RABs have received increasing attention in cancer research. However, the functional roles of exocytic RABs in colorectal carcinogenesis remain to be elucidated. METHODS: Immunohistochemistry analysis of a microarray containing 215 colorectal adenocarcinoma tissues was used to identify the association between exocytic RABs and patient prognosis. Complementary functional RAB3C overexpression and knockdown experiments were performed. The molecular mechanism of RAB3C in inducing colon cancer cell metastasis was determined. RESULTS: High RAB3C expression in patients was found to be significantly associated with advanced pathological stage, distant metastasis and poor prognosis. Multivariate analyses showed that high RAB3C expression was an independent prognostic marker in overall (P = 0.001) and disease-free survival (P < 0.001). Furthermore, our experimental results showed an increase in the migration and invasion ability of RAB3C-overexpressing colon cancer cells and increased metastatic nodules in a mouse metastasis model. The effect of RAB3C-overexpressing cell-conditioned medium was found to significantly promote the migration ability of parental colon cancer cells, thus suggesting that the promotion of migration is exocytosis dependent. Upregulation of other exocytic RABs was also seen in RAB3C-overexpressing cells. Through microarray and proteomics analyses, increased production of multiple cytokines was observed in RAB3C-overexpressing cell lines, and the IL-6 pathway was the top pathway whose members exhibited gene expression changes after RAB3C overexpression, according to Ingenuity Pathway Analysis. Blocking IL-6 with IL-6 antibody treatment or IL-6 knockdown significantly inhibited the migration potential of RAB3C-overexpressing colon cancer cells. In addition, IL-6 was found to induce STAT3 phosphorylation in RAB3C-overexpressing colon cancer cells, thus promoting migration. Ruxolitinib, a JAK2 inhibitor, was found to significantly inhibit RAB3C-induced colon cancer cell migration. CONCLUSIONS: Our study revealed that RAB3C overexpression promotes tumor metastasis and is associated with poor prognosis in colorectal cancer, through modulating the ability of cancer cells to release IL-6 through exocytosis and activate the JAK2-STAT3 signaling pathway. These results further suggest that inhibition of STAT3 phosphorylation in the RAB3C-IL-6-STAT3 axis by using Ruxolitinib may be a new therapeutic strategy to combat metastatic colon cancers.

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  • Elevated expression of RAB3C promotes in vivo migration, invasion, and metastasis of colorectal cancer.

    “Elevated expression of RAB3C promotes in vivo migration, invasion, and metastasis of colorectal cancer while RAB3D induced breast cancer cell invasion by activating Akt/GSK-3β/Snail pathway [115,116].”

    From Insights of Endocytosis Signaling in Health and Disease (2023) · cites this paper as [115]

    The Background (page not provided) distinguishes increased migration and invasion in vitro from metastasis-promoting ability in vivo. The Results report cell migration and invasion assays and increased metastatic nodules in mice. The source therefore supports in vivo metastasis, but not the claim that migration and invasion were demonstrated in vivo. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • RAB3D induces breast cancer cell invasion by activating Akt/GSK-3β/Snail pathway.

    “Elevated expression of RAB3C promotes in vivo migration, invasion, and metastasis of colorectal cancer while RAB3D induced breast cancer cell invasion by activating Akt/GSK-3β/Snail pathway [115,116].”

    From Insights of Endocytosis Signaling in Health and Disease (2023) · cites this paper as [115]

    The Discussion (page unavailable) mentions RAB3D in breast cancer but says only that endogenous RAB3D expression was not correlated with tumor progression. A search for RAB3D and the Akt/GSK-3β/Snail pathway found no passage in our copy addressing whether RAB3D induces breast cancer cell invasion through that pathway. The paper’s invasion and metastasis findings concern RAB3C in colorectal cancer. (LLM, conf=0.76)

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Research works printed but not linked: 45

  1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62:10–29. · DOI · Paper page
  2. Sung JJ, Lau JY, Goh KL, Leung WK. Increasing incidence of colorectal cancer in Asia: implications for screening. Lancet Oncol. 2005;6:871–6. · DOI
  3. Cunningham D, Atkin W, Lenz HJ, Lynch HT, Minsky B, Nordlinger B, Starling N. Colorectal cancer. Lancet. 2010;375:1030–47. · DOI
  4. Hutagalung AH, Novick PJ. Role of Rab GTPases in membrane traffic and cell physiology. Physiol Rev. 2011;91:119–49. · DOI · Paper page
  5. Cooper AA, Gitler AD, Cashikar A, Haynes CM, Hill KJ, Bhullar B, Liu K, Xu K, Strathearn KE, Liu F, et al. Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson's models. Science. 2006;313:324–8. · DOI
  6. Gitler AD, Bevis BJ, Shorter J, Strathearn KE, Hamamichi S, Su LJ, Caldwell KA, Caldwell GA, Rochet JC, McCaffery JM, et al. The Parkinson's disease protein alpha-synuclein disrupts cellular Rab homeostasis. Proc Natl Acad Sci U S A. 2008;105:145–50. · DOI
  7. Li X, Standley C, Sapp E, Valencia A, Qin ZH, Kegel KB, Yoder J, Comer-Tierney LA, Esteves M, Chase K, et al. Mutant huntingtin impairs vesicle formation from recycling endosomes by interfering with Rab11 activity. Mol Cell Biol. 2009;29:6106–16. · DOI · Paper page
  8. Sano H, Roach WG, Peck GR, Fukuda M, Lienhard GE. Rab10 in insulin-stimulated GLUT4 translocation. Biochem J. 2008;411:89–95. · DOI
  9. Kitano M, Nakaya M, Nakamura T, Nagata S, Matsuda M. Imaging of Rab5 activity identifies essential regulators for phagosome maturation. Nature. 2008;453:241–5. · DOI
  10. Machner MP, Isberg RR. A bifunctional bacterial protein links GDI displacement to Rab1 activation. Science. 2007;318:974–7. · DOI
  11. Goldenring JR, Shen KR, Vaughan HD, Modlin IM. Identification of a small GTP-binding protein, Rab25, expressed in the gastrointestinal mucosa, kidney, and lung. J Biol Chem. 1993;268:18419–22. · DOI
  12. Caswell PT, Spence HJ, Parsons M, White DP, Clark K, Cheng KW, Mills GB, Humphries MJ, Messent AJ, Anderson KI, et al. Rab25 associates with alpha5beta1 integrin to promote invasive migration in 3D microenvironments. Dev Cell. 2007;13:496–510. · DOI
  13. Goldenring JR, Nam KT. Rab25 as a tumour suppressor in colon carcinogenesis. Br J Cancer. 2011;104:33–6. · DOI
  14. Tang BL, Ng EL. Rabs and cancer cell motility. Cell Motil Cytoskeleton. 2009;66:365–70. · DOI
  15. Cheng KW, Lahad JP, Kuo WL, Lapuk A, Yamada K, Auersperg N, Liu J, Smith-McCune K, Lu KH, Fishman D, et al. The RAB25 small GTPase determines aggressiveness of ovarian and breast cancers. Nat Med. 2004;10:1251–6. · DOI
  16. Yin YX, Shen F, Pei H, Ding Y, Zhao H, Zhao M, Chen Q. Increased expression of Rab25 in breast cancer correlates with lymphatic metastasis. Tumour Biol. 2012;33:1581–7. · DOI
  17. Torres VA, Mielgo A, Barbero S, Hsiao R, Wilkins JA, Stupack DG. Rab5 mediates caspase-8-promoted cell motility and metastasis. Mol Biol Cell. 2010;21:369–76. · DOI
  18. Frittoli E, Palamidessi A, Marighetti P, Confalonieri S, Bianchi F, Malinverno C, Mazzarol G, Viale G, Martin-Padura I, Garre M, et al. A RAB5/RAB4 recycling circuitry induces a proteolytic invasive program and promotes tumor dissemination. J Cell Biol. 2014;206:307–28. · DOI
  19. Palamidessi A, Frittoli E, Ducano N, Offenhauser N, Sigismund S, Kajiho H, Parazzoli D, Oldani A, Gobbi M, Serini G, et al. The GTPase-activating protein RN-tre controls focal adhesion turnover and cell migration. Curr Biol. 2013;23:2355–64. · DOI
  20. Palamidessi A, Frittoli E, Garre M, Faretta M, Mione M, Testa I, Diaspro A, Lanzetti L, Scita G, Di Fiore PP. Endocytic trafficking of Rac is required for the spatial restriction of signaling in cell migration. Cell. 2008;134:135–47. · DOI
  21. Fukui K, Tamura S, Wada A, Kamada Y, Igura T, Kiso S, Hayashi N. Expression of Rab5a in hepatocellular carcinoma: Possible involvement in epidermal growth factor signaling. Hepatol Res. 2007;37:957–65. · DOI
  22. Li Y, Meng X, Feng H, Zhang G, Liu C, Li P. Over-expression of the RAB5 gene in human lung adenocarcinoma cells with high metastatic potential. Chin Med Sci J. 1999;14:96–101.
  23. Hendrix A, Maynard D, Pauwels P, Braems G, Denys H, Van den Broecke R, Lambert J, Van Belle S, Cocquyt V, Gespach C, et al. Effect of the secretory small GTPase Rab27B on breast cancer growth, invasion, and metastasis. J Natl Cancer Inst. 2010;102:866–80. · DOI
  24. Wang JS, Wang FB, Zhang QG, Shen ZZ, Shao ZM. Enhanced expression of Rab27A gene by breast cancer cells promoting invasiveness and the metastasis potential by secretion of insulin-like growth factor-II. Mol Cancer Res. 2008;6:372–82. · DOI
  25. Geppert M, Goda Y, Stevens CF, Sudhof TC. The small GTP-binding protein Rab3A regulates a late step in synaptic vesicle fusion. Nature. 1997;387:810–4. · DOI
  26. Millar AL, Pavios NJ, Xu J, Zheng MH. Rab3D: a regulator of exocytosis in non-neuronal cells. Histol Histopathol. 2002;17:929–36.
  27. Weber E, Jilling T, Kirk KL. Distinct functional properties of Rab3A and Rab3B in PC12 neuroendocrine cells. J Biol Chem. 1996;271:6963–71. · DOI
  28. Dai S, Wei D, Wu Z, Zhou X, Wei X, Huang H, Li G. Phase I clinical trial of autologous ascites-derived exosomes combined with GM-CSF for colorectal cancer. Mol Ther. 2008;16:782–90. · DOI
  29. Silva J, Garcia V, Rodriguez M, Compte M, Cisneros E, Veguillas P, Garcia JM, Dominguez G, Campos-Martin Y, Cuevas J, et al. Analysis of exosome release and its prognostic value in human colorectal cancer. Genes Chromosomes Cancer. 2012;51:409–18. · DOI
  30. Chavrier P, Gorvel JP, Stelzer E, Simons K, Gruenberg J, Zerial M. Hypervariable C-terminal domain of rab proteins acts as a targeting signal. Nature. 1991;353:769–72. · DOI
  31. Steele-Mortimer O, Clague MJ, Huber LA, Chavrier P, Gruenberg J, Gorvel JP. The N-terminal domain of a rab protein is involved in membrane-membrane recognition and/or fusion. EMBO J. 1994;13:34–41. · DOI
  32. Lledo PM, Vernier P, Vincent JD, Mason WT, Zorec R. Inhibition of Rab3B expression attenuates Ca(2+)-dependent exocytosis in rat anterior pituitary cells. Nature. 1993;364:540–4. · DOI
  33. Rotondo F, Scheithauer BW, Kovacs K, Bell DC. Rab3B immunoexpression in human pituitary adenomas. Appl Immunohistochem Mol Morphol. 2009;17:185–8. · DOI
  34. Schluter OM, Khvotchev M, Jahn R, Sudhof TC. Localization versus function of Rab3 proteins. Evidence for a common regulatory role in controlling fusion. J Biol Chem. 2002;277:40919–29. · DOI
  35. Ara T, Declerck YA. Interleukin-6 in bone metastasis and cancer progression. Eur J Cancer. 2010;46:1223–31. · DOI
  36. Guo Y, Xu F, Lu T, Duan Z, Zhang Z. Interleukin-6 signaling pathway in targeted therapy for cancer. Cancer Treat Rev. 2012;38:904–10. · DOI
  37. West NR, McCuaig S, Franchini F, Powrie F. Emerging cytokine networks in colorectal cancer. Nat Rev Immunol. 2015;15:615–29. · DOI
  38. Chung YC, Chaen YL, Hsu CP. Clinical significance of tissue expression of interleukin-6 in colorectal carcinoma. Anticancer Res. 2006;26:3905–11.
  39. Nagasaki T, Hara M, Nakanishi H, Takahashi H, Sato M, Takeyama H. Interleukin-6 released by colon cancer-associated fibroblasts is critical for tumour angiogenesis: anti-interleukin-6 receptor antibody suppressed angiogenesis and inhibited tumour-stroma interaction. Br J Cancer. 2014;110:469–78. · DOI
  40. Sansone P, Storci G, Tavolari S, Guarnieri T, Giovannini C, Taffurelli M, Ceccarelli C, Santini D, Paterini P, Marcu KB, et al. IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland. J Clin Invest. 2007;117:3988–4002. · DOI · Paper page
  41. Hendrix A, Hume AN. Exosome signaling in mammary gland development and cancer. Int J Dev Biol. 2011;55:879–87. · DOI
  42. Ostrowski M, Carmo NB, Krumeich S, Fanget I, Raposo G, Savina A, Moita CF, Schauer K, Hume AN, Freitas RP, et al: Rab27a and Rab27b control different steps of the exosome secretion pathway. Nat Cell Biol 2010, 12:19–30; sup pp 11-13. · DOI
  43. Ji H, Greening DW, Barnes TW, Lim JW, Tauro BJ, Rai A, Xu R, Adda C, Mathivanan S, Zhao W, et al. Proteome profiling of exosomes derived from human primary and metastatic colorectal cancer cells reveal differential expression of key metastatic factors and signal transduction components. Proteomics. 2013;13:1672–86. · DOI
  44. Iero M, Valenti R, Huber V, Filipazzi P, Parmiani G, Fais S, Rivoltini L. Tumour-released exosomes and their implications in cancer immunity. Cell Death Differ. 2008;15:80–8. · DOI
  45. Shedden K, Xie XT, Chandaroy P, Chang YT, Rosania GR. Expulsion of small molecules in vesicles shed by cancer cells: association with gene expression and chemosensitivity profiles. Cancer Res. 2003;63:4331–7.

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Metadata

Authors
Chang, Y.-C., Su, C.-Y., Chen, M.-H., Chen, W.-S., Chen, C.-L., & Hsiao, M.
Affiliations
  • Genomics Research Center, Academia Sinica (TW)
  • Taipei Veterans General Hospital (TW)
  • Taipei Medical University Hospital (TW)
  • Kaohsiung Medical University (TW)
Corresponding author
  • Chen, Wei-Shone
  • Chen, Chi-Long
  • Hsiao, Michael
ORCID
Venue
Molecular Cancer
Publisher
Springer Science and Business Media LLC
Published
2017-08-07
Volume
16
Issue
1
Pages
135-135
ISSN
1476-4598 (ISSN-L)
DOI
10.1186/s12943-017-0687-7
PMC
PMC5547507
OpenAlex
W2742632885
Cited by
74
References
2
Citations by year
2026: 1 · 2025: 6 · 2024: 9 · 2023: 10 · 2022: 6 · 2021: 12 · 2020: 14 · 2019: 9 · 2018: 6 · 2017: 1
FWCI
4.38
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Molecular Cancer (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Ministry of Science and Technology, Taiwan (MOST 104-0210-01-09-02, MOST 105-0210-01-13-01, MOST 106-0210-01-15-02)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
Keywords
Rab3C, colorectal cancer, colon cancer metastasis, interleukin-6, STAT3 signaling, JAK2 inhibition, ruxolitinib, exocytosis, tumor cell migration and invasion, prognostic factors, conditioned medium, membrane trafficking, disease-free survival
MeSH terms
Animals, Cell Movement, Colonic Neoplasms, Humans, Immunohistochemistry, Male, Neoplasm Invasiveness, Prognosis, Interleukin-6, rab3 GTP-Binding Proteins, Cell Line, Tumor, STAT3 Transcription Factor, Mice, Heterografts

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