Skip to main content
Top
Published in: BMC Cancer 1/2023

Open Access 01-12-2023 | Hepatocellular Carcinoma | Research

Elevated FAM134B expression induces radiation-sensitive in hepatocellular carcinoma

Authors: Binhui Xie, Yuankang Xie, Cuifu Fang, Baiyin Zhong, Rong Ye, Jianhong Zhang, Qingquan Liu, Heping Li

Published in: BMC Cancer | Issue 1/2023

Login to get access

Abstract

Background

Previous studies have shown that Family with sequence similarity 134 member B (FAM134B) was involved in the occurrence and development of malignancy, however, the function and molecular mechanism of FAM134B in Hepatocellular Carcinoma (HCC) radiotherapy resistance remain unclear. Therefore, it may clinical effective to clarify the molecular mechanism and identify novel biomarker to overcome radiotherapy resistance in HCC.

Methods

The protein and mRNA expression of FAM134B were determined using Real-time PCR and Western blot, respectively. IHC assay was performed to investigate the association between FAM134B expression and the clinicopathological characteristics of 132 HCC patients. Functional assays, such as in situ model, colon formation, FACS, and Tunel assay were used to determine the oncogenic role of FAM134B in human HCC progression. Furthermore, western blotting and luciferase assay were used to determine the mechanism of FAM134B promotes radiation-sensitive in HCC cells.

Results

We noted that FAM134B was downregulated in HCC, which was correlated with the radiation resistance in patients with HCC. Overexpression of FAM134B contribute to radiation sensitive in HCC; however, inhibition of FAM134B confers HCC cell lines to radiation resistance both in vitro and in vivo. Moreover, we found that FAM134B interacts with FMS related receptor tyrosine kinase 3 (FLT3) and downregulation of FAM134B activated JAK/Stat3 signaling pathway. Importantly, pharmacological inhibition of JAK/Stat3 signaling pathway significantly counteracted downregulation of FAM134B-induced radiation resistance and enhanced radiation therapeutic efficacy in HCC.

Conclusions

Our findings suggest that FAM134B may be a potential therapeutic biomarker for the treatment of HCC patients with radiotherapy tolerance.
Appendix
Available only for authorised users
Literature
1.
go back to reference Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359–386.CrossRefPubMed Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359–386.CrossRefPubMed
2.
go back to reference Marengo A, Rosso C, Bugianesi E. Liver Cancer: connections with obesity, fatty liver, and cirrhosis. Annu Rev Med. 2016;67:103–17.CrossRefPubMed Marengo A, Rosso C, Bugianesi E. Liver Cancer: connections with obesity, fatty liver, and cirrhosis. Annu Rev Med. 2016;67:103–17.CrossRefPubMed
3.
go back to reference Clark T, Maximin S, Meier J, Pokharel S, Bhargava P. Hepatocellular Carcinoma: review of Epidemiology, Screening, Imaging diagnosis, Response Assessment, and treatment. Curr Probl Diagn Radiol. 2015;44(6):479–86.CrossRefPubMed Clark T, Maximin S, Meier J, Pokharel S, Bhargava P. Hepatocellular Carcinoma: review of Epidemiology, Screening, Imaging diagnosis, Response Assessment, and treatment. Curr Probl Diagn Radiol. 2015;44(6):479–86.CrossRefPubMed
4.
go back to reference Ghouri YA, Mian I, Rowe JH. Review of hepatocellular carcinoma: epidemiology, etiology, and carcinogenesis. J Carcinog 2017, 16:1. Ghouri YA, Mian I, Rowe JH. Review of hepatocellular carcinoma: epidemiology, etiology, and carcinogenesis. J Carcinog 2017, 16:1.
5.
go back to reference Wahl DR, Stenmark MH, Tao Y, Pollom EL, Caoili EM, Lawrence TS, Schipper MJ, Feng M. Outcomes after stereotactic body radiotherapy or Radiofrequency ablation for Hepatocellular Carcinoma. J Clin oncology: official J Am Soc Clin Oncol. 2016;34(5):452–9.CrossRef Wahl DR, Stenmark MH, Tao Y, Pollom EL, Caoili EM, Lawrence TS, Schipper MJ, Feng M. Outcomes after stereotactic body radiotherapy or Radiofrequency ablation for Hepatocellular Carcinoma. J Clin oncology: official J Am Soc Clin Oncol. 2016;34(5):452–9.CrossRef
6.
go back to reference Wang J, Li Q, Sun Y, Zheng H, Cui Y, Li H, Zhou H, Hao X. Clinicopathologic features between multicentric occurence and intrahepatic metastasis of multiple hepatocellular carcinomas related to HBV. Surg Oncol. 2009;18(1):25–30.CrossRefPubMed Wang J, Li Q, Sun Y, Zheng H, Cui Y, Li H, Zhou H, Hao X. Clinicopathologic features between multicentric occurence and intrahepatic metastasis of multiple hepatocellular carcinomas related to HBV. Surg Oncol. 2009;18(1):25–30.CrossRefPubMed
7.
go back to reference Couri T, Pillai A. Goals and targets for personalized therapy for HCC. Hep Intl. 2019;13(2):125–37.CrossRef Couri T, Pillai A. Goals and targets for personalized therapy for HCC. Hep Intl. 2019;13(2):125–37.CrossRef
8.
go back to reference Kishore SA, Bajwa R, Madoff DC. Embolotherapeutic strategies for Hepatocellular Carcinoma: 2020 update. Cancers 2020, 12(4). Kishore SA, Bajwa R, Madoff DC. Embolotherapeutic strategies for Hepatocellular Carcinoma: 2020 update. Cancers 2020, 12(4).
9.
go back to reference Lee SY, Jeong EK, Ju MK, Jeon HM, Kim MY, Kim CH, Park HG, Han SI, Kang HS. Induction of metastasis, cancer stem cell phenotype, and oncogenic metabolism in cancer cells by ionizing radiation. Mol Cancer. 2017;16(1):10.CrossRefPubMedPubMedCentral Lee SY, Jeong EK, Ju MK, Jeon HM, Kim MY, Kim CH, Park HG, Han SI, Kang HS. Induction of metastasis, cancer stem cell phenotype, and oncogenic metabolism in cancer cells by ionizing radiation. Mol Cancer. 2017;16(1):10.CrossRefPubMedPubMedCentral
10.
go back to reference Fu SM, Xu MX, Lin SM, Liang Z, Cai JH. Association of cyclin D1 and survivin expression with sensitivity to radiotherapy in patients with nasopharyngeal carcinoma. Genet Mol research: GMR. 2014;13(2):3502–9.CrossRefPubMed Fu SM, Xu MX, Lin SM, Liang Z, Cai JH. Association of cyclin D1 and survivin expression with sensitivity to radiotherapy in patients with nasopharyngeal carcinoma. Genet Mol research: GMR. 2014;13(2):3502–9.CrossRefPubMed
12.
go back to reference Sehedic D, Cikankowitz A, Hindre F, Davodeau F, Garcion E. Nanomedicine to overcome radioresistance in glioblastoma stem-like cells and surviving clones. Trends Pharmacol Sci. 2015;36(4):236–52.CrossRefPubMed Sehedic D, Cikankowitz A, Hindre F, Davodeau F, Garcion E. Nanomedicine to overcome radioresistance in glioblastoma stem-like cells and surviving clones. Trends Pharmacol Sci. 2015;36(4):236–52.CrossRefPubMed
13.
go back to reference Sun Q, Liu T, Zhang T, Du S, Xie GX, Lin X, Chen L, Yuan Y. MiR-101 sensitizes human nasopharyngeal carcinoma cells to radiation by targeting stathmin 1. Mol Med Rep. 2015;11(5):3330–6.CrossRefPubMedPubMedCentral Sun Q, Liu T, Zhang T, Du S, Xie GX, Lin X, Chen L, Yuan Y. MiR-101 sensitizes human nasopharyngeal carcinoma cells to radiation by targeting stathmin 1. Mol Med Rep. 2015;11(5):3330–6.CrossRefPubMedPubMedCentral
14.
go back to reference Islam F, Gopalan V, Lam AK. RETREG1 (FAM134B): a new player in human diseases: 15 years after the discovery in cancer. J Cell Physiol. 2018;233(6):4479–89.CrossRefPubMed Islam F, Gopalan V, Lam AK. RETREG1 (FAM134B): a new player in human diseases: 15 years after the discovery in cancer. J Cell Physiol. 2018;233(6):4479–89.CrossRefPubMed
15.
go back to reference Islam F, Gopalan V, Law S, Tang JC, Lam AK. FAM134B promotes esophageal squamous cell carcinoma in vitro and its correlations with clinicopathologic features. Hum Pathol. 2019;87:1–10.CrossRefPubMed Islam F, Gopalan V, Law S, Tang JC, Lam AK. FAM134B promotes esophageal squamous cell carcinoma in vitro and its correlations with clinicopathologic features. Hum Pathol. 2019;87:1–10.CrossRefPubMed
16.
go back to reference Haque MH, Gopalan V, Chan KW, Shiddiky MJ, Smith RA, Lam AK. Identification of Novel FAM134B (JK1) mutations in Oesophageal squamous cell carcinoma. Sci Rep. 2016;6:29173.CrossRefPubMedPubMedCentral Haque MH, Gopalan V, Chan KW, Shiddiky MJ, Smith RA, Lam AK. Identification of Novel FAM134B (JK1) mutations in Oesophageal squamous cell carcinoma. Sci Rep. 2016;6:29173.CrossRefPubMedPubMedCentral
18.
go back to reference Oakes SA, Papa FR. The role of endoplasmic reticulum stress in human pathology. Annu Rev Pathol. 2015;10:173–94.CrossRefPubMed Oakes SA, Papa FR. The role of endoplasmic reticulum stress in human pathology. Annu Rev Pathol. 2015;10:173–94.CrossRefPubMed
19.
go back to reference Yamasaki S, Yagishita N, Nishioka K, Nakajima T. The roles of synoviolin in crosstalk between endoplasmic reticulum stress-induced apoptosis and p53 pathway. Cell Cycle. 2007;6(11):1319–23.CrossRefPubMed Yamasaki S, Yagishita N, Nishioka K, Nakajima T. The roles of synoviolin in crosstalk between endoplasmic reticulum stress-induced apoptosis and p53 pathway. Cell Cycle. 2007;6(11):1319–23.CrossRefPubMed
20.
go back to reference Zhang ZQ, Chen J, Huang WQ, Ning D, Liu QM, Wang C, Zhang L, Ren L, Chu L, Liang HF, et al. FAM134B induces tumorigenesis and epithelial-to-mesenchymal transition via akt signaling in hepatocellular carcinoma. Mol Oncol. 2019;13(4):792–810.CrossRefPubMedPubMedCentral Zhang ZQ, Chen J, Huang WQ, Ning D, Liu QM, Wang C, Zhang L, Ren L, Chu L, Liang HF, et al. FAM134B induces tumorigenesis and epithelial-to-mesenchymal transition via akt signaling in hepatocellular carcinoma. Mol Oncol. 2019;13(4):792–810.CrossRefPubMedPubMedCentral
21.
go back to reference Forman OP, Hitti RJ, Pettitt L, Jenkins CA, O’Brien DP, Shelton GD, De Risio L, Quintana RG, Beltran E, Mellersh C. An inversion disrupting FAM134B is Associated with sensory neuropathy in the Border Collie Dog Breed. G3. 2016;6(9):2687–92.CrossRefPubMedPubMedCentral Forman OP, Hitti RJ, Pettitt L, Jenkins CA, O’Brien DP, Shelton GD, De Risio L, Quintana RG, Beltran E, Mellersh C. An inversion disrupting FAM134B is Associated with sensory neuropathy in the Border Collie Dog Breed. G3. 2016;6(9):2687–92.CrossRefPubMedPubMedCentral
22.
go back to reference Kuvshinoff BW, Ota DM. Radiofrequency ablation of liver tumors: influence of technique and tumor size. Surgery. 2002;132(4):605–11. discussion 611 – 602.CrossRefPubMed Kuvshinoff BW, Ota DM. Radiofrequency ablation of liver tumors: influence of technique and tumor size. Surgery. 2002;132(4):605–11. discussion 611 – 602.CrossRefPubMed
23.
go back to reference Li Q, Wang J, Juzi JT, Sun Y, Zheng H, Cui Y, Li H, Hao X. Clonality analysis for multicentric origin and intrahepatic metastasis in recurrent and primary hepatocellular carcinoma. J Gastrointest surgery: official J Soc Surg Aliment Tract. 2008;12(9):1540–7.CrossRef Li Q, Wang J, Juzi JT, Sun Y, Zheng H, Cui Y, Li H, Hao X. Clonality analysis for multicentric origin and intrahepatic metastasis in recurrent and primary hepatocellular carcinoma. J Gastrointest surgery: official J Soc Surg Aliment Tract. 2008;12(9):1540–7.CrossRef
24.
go back to reference Davila JA, Duan Z, McGlynn KA, El-Serag HB. Utilization and outcomes of palliative therapy for hepatocellular carcinoma: a population-based study in the United States. J Clin Gastroenterol. 2012;46(1):71–7.CrossRefPubMed Davila JA, Duan Z, McGlynn KA, El-Serag HB. Utilization and outcomes of palliative therapy for hepatocellular carcinoma: a population-based study in the United States. J Clin Gastroenterol. 2012;46(1):71–7.CrossRefPubMed
25.
go back to reference Schwarz RE, Smith DD. Trends in local therapy for hepatocellular carcinoma and survival outcomes in the US population. Am J Surg. 2008;195(6):829–36.CrossRefPubMed Schwarz RE, Smith DD. Trends in local therapy for hepatocellular carcinoma and survival outcomes in the US population. Am J Surg. 2008;195(6):829–36.CrossRefPubMed
26.
go back to reference Boriachek K, Islam MN, Gopalan V, Lam AK, Nguyen NT, Shiddiky MJA. Quantum dot-based sensitive detection of disease specific exosome in serum. Analyst. 2017;142(12):2211–9.CrossRefPubMed Boriachek K, Islam MN, Gopalan V, Lam AK, Nguyen NT, Shiddiky MJA. Quantum dot-based sensitive detection of disease specific exosome in serum. Analyst. 2017;142(12):2211–9.CrossRefPubMed
27.
go back to reference Kasem K, Sullivan E, Gopalan V, Salajegheh A, Smith RA, Lam AK. JK1 (FAM134B) represses cell migration in colon cancer: a functional study of a novel gene. Exp Mol Pathol. 2014;97(1):99–104.CrossRefPubMed Kasem K, Sullivan E, Gopalan V, Salajegheh A, Smith RA, Lam AK. JK1 (FAM134B) represses cell migration in colon cancer: a functional study of a novel gene. Exp Mol Pathol. 2014;97(1):99–104.CrossRefPubMed
28.
go back to reference Islam F, Gopalan V, Wahab R, Smith RA, Qiao B, Lam AK. Stage dependent expression and tumor suppressive function of FAM134B (JK1) in colon cancer. Mol Carcinog. 2017;56(1):238–49.CrossRefPubMed Islam F, Gopalan V, Wahab R, Smith RA, Qiao B, Lam AK. Stage dependent expression and tumor suppressive function of FAM134B (JK1) in colon cancer. Mol Carcinog. 2017;56(1):238–49.CrossRefPubMed
29.
go back to reference Islam F, Gopalan V, Pillai S, Lu CT, Kasem K, Lam AK. Promoter hypermethylation inactivate tumor suppressor FAM134B and is associated with poor prognosis in colorectal cancer. Genes Chromosomes Cancer. 2018;57(5):240–51.CrossRefPubMed Islam F, Gopalan V, Pillai S, Lu CT, Kasem K, Lam AK. Promoter hypermethylation inactivate tumor suppressor FAM134B and is associated with poor prognosis in colorectal cancer. Genes Chromosomes Cancer. 2018;57(5):240–51.CrossRefPubMed
30.
go back to reference Corcoran RB, Contino G, Deshpande V, Tzatsos A, Conrad C, Benes CH, Levy DE, Settleman J, Engelman JA, Bardeesy N. STAT3 plays a critical role in KRAS-induced pancreatic tumorigenesis. Cancer Res. 2011;71(14):5020–9.CrossRefPubMedPubMedCentral Corcoran RB, Contino G, Deshpande V, Tzatsos A, Conrad C, Benes CH, Levy DE, Settleman J, Engelman JA, Bardeesy N. STAT3 plays a critical role in KRAS-induced pancreatic tumorigenesis. Cancer Res. 2011;71(14):5020–9.CrossRefPubMedPubMedCentral
31.
go back to reference Hussain SF, Kong LY, Jordan J, Conrad C, Madden T, Fokt I, Priebe W, Heimberger AB. A novel small molecule inhibitor of signal transducers and activators of transcription 3 reverses immune tolerance in malignant glioma patients. Cancer Res. 2007;67(20):9630–6.CrossRefPubMed Hussain SF, Kong LY, Jordan J, Conrad C, Madden T, Fokt I, Priebe W, Heimberger AB. A novel small molecule inhibitor of signal transducers and activators of transcription 3 reverses immune tolerance in malignant glioma patients. Cancer Res. 2007;67(20):9630–6.CrossRefPubMed
32.
go back to reference Iwamaru A, Szymanski S, Iwado E, Aoki H, Yokoyama T, Fokt I, Hess K, Conrad C, Madden T, Sawaya R, et al. A novel inhibitor of the STAT3 pathway induces apoptosis in malignant glioma cells both in vitro and in vivo. Oncogene. 2007;26(17):2435–44.CrossRefPubMed Iwamaru A, Szymanski S, Iwado E, Aoki H, Yokoyama T, Fokt I, Hess K, Conrad C, Madden T, Sawaya R, et al. A novel inhibitor of the STAT3 pathway induces apoptosis in malignant glioma cells both in vitro and in vivo. Oncogene. 2007;26(17):2435–44.CrossRefPubMed
33.
go back to reference Chen X, Ying Z, Lin X, Lin H, Wu J, Li M, Song L. Acylglycerol kinase augments JAK2/STAT3 signaling in esophageal squamous cells. J Clin Investig. 2013;123(6):2576–89.CrossRefPubMedPubMedCentral Chen X, Ying Z, Lin X, Lin H, Wu J, Li M, Song L. Acylglycerol kinase augments JAK2/STAT3 signaling in esophageal squamous cells. J Clin Investig. 2013;123(6):2576–89.CrossRefPubMedPubMedCentral
Metadata
Title
Elevated FAM134B expression induces radiation-sensitive in hepatocellular carcinoma
Authors
Binhui Xie
Yuankang Xie
Cuifu Fang
Baiyin Zhong
Rong Ye
Jianhong Zhang
Qingquan Liu
Heping Li
Publication date
01-12-2023
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2023
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-023-11030-x

Other articles of this Issue 1/2023

BMC Cancer 1/2023 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine