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Holmlund, Birgitta
Publications (10 of 14) Show all publications
Liu, N., Cox, T. R., Cui, W., Adell, G., Holmlund, B., Ping, J., . . . Sun, X.-F. (2017). Nuclear expression of lysyl oxidase enzyme is an independent prognostic factor in rectal cancer patients.. OncoTarget, 8(36), 60015-60024
Open this publication in new window or tab >>Nuclear expression of lysyl oxidase enzyme is an independent prognostic factor in rectal cancer patients.
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2017 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 36, p. 60015-60024Article in journal (Refereed) Published
Abstract [en]

Emerging evidence has implicated a pivotal role for lysyl oxidase (LOX) in cancer progression and metastasis. Whilst the majority of work has focused on the extracellular matrix cross-linking role of LOX, the exact function of intracellular LOX localisation remains unclear. In this study, we analysed the LOX expression patterns in the nuclei of rectal cancer patient samples and determined the clinical significance of this expression. Nuclear LOX expression was significantly increased in patient lymph node metastases compared to their primary tumours. High nuclear LOX expression in tumours was correlated with a high rate of distant metastasis and increased recurrence. Multivariable analysis showed that high nuclear LOX expression was also correlated with poor overall survival and disease free survival. Furthermore, we are the first to identify LOX enzyme isoforms (50 kDa and 32 kDa) within the nucleus of colon cancer cell lines by confocal microscopy and Western blot. Our results show a powerful link between nuclear LOX expression in tumours and patient survival, and offer a promising prognostic biomarker for rectal cancer patients.

Place, publisher, year, edition, pages
Impact journals, 2017
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-134762 (URN)10.18632/oncotarget.9623 (DOI)000408944300001 ()27231855 (PubMedID)
Note

Funding agencies: Swedish Cancer Foundation; Research Council of South East Sweden; Liu Cancer

Available from: 2017-02-24 Created: 2017-02-24 Last updated: 2018-05-03
Meng, W.-J., Pathak, S., Ding, Z.-Y., Zhang, H., Adell, G., Holmlund, B., . . . Sun, X.-F. (2015). Special AT-rich sequence binding protein 1 expression correlates with response to preoperative radiotherapy and clinical outcome in rectal cancer. Cancer Biology & Therapy, 16(12), 1738-1745
Open this publication in new window or tab >>Special AT-rich sequence binding protein 1 expression correlates with response to preoperative radiotherapy and clinical outcome in rectal cancer
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2015 (English)In: Cancer Biology & Therapy, ISSN 1538-4047, E-ISSN 1555-8576, Vol. 16, no 12, p. 1738-1745Article in journal (Refereed) Published
Abstract [en]

Our recent study showed the important role of special AT-rich sequence binding protein 1 (SATB1) in the progression of human rectal cancer. However, the value of SATB1 in response to radiotherapy (RT) for rectal cancer hasnt been reported so far. Here, SATB1 was determined using immunohistochemistry in normal mucosa, biopsy, primary cancer, and lymph node metastasis from 132 rectal cancer patients: 66 with and 66 without preoperative RT before surgery. The effect of SATB1 knockdown on radiosensitivity was assessed by proliferation-based assay and clonogenic assay. The results showed that SATB1 increased from normal mucosa to primary cancer, whereas it decreased from primary cancer to metastasis in non-RT patients. SATB1 decreased in primary cancers after RT. In RT patients, positive SATB1 was independently associated with decreased response to preoperative RT, early time to metastasis, and worse survival. SATB1 negatively correlated with ataxia telangiectasia mutated (ATM) and pRb2/p130, and positively with Ki-67 and Survivin in RT patients, and their potential interaction through different canonical pathways was identified in network ideogram. Taken together, our findings disclose for the first time that radiation decreases SATB1 expression and sensitizes cancer cells to confer clinical benefit of patients, suggesting that SATB1 is predictive of response to preoperative RT and clinical outcome in rectal cancer.

Place, publisher, year, edition, pages
TAYLOR & FRANCIS INC, 2015
Keywords
colorectal cancer; Ingenuity Pathway Analysis; preoperative radiotherapy; prognosis; SATB1
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-125837 (URN)10.1080/15384047.2015.1095408 (DOI)000369916100007 ()26528635 (PubMedID)
Note

Funding Agencies|Swedish Cancer Foundation; Swedish Research Council; Health Research Council in the South-East of Sweden

Available from: 2016-03-08 Created: 2016-03-04 Last updated: 2018-03-23
Pathak, S., Zhang, H., Gnosa, S., Kumar Nandy, S., Adell, G., Holmlund, B. & Sun, X.-F. (2014). Tafazzin protein expression is associated with tumorigenesis and radiation response in rectal cancer: a study of Swedish clinical trial on preoperative radiotherapy.. PLoS ONE, 9(5), e98317
Open this publication in new window or tab >>Tafazzin protein expression is associated with tumorigenesis and radiation response in rectal cancer: a study of Swedish clinical trial on preoperative radiotherapy.
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2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 5, p. e98317-Article in journal (Refereed) Published
Abstract [en]

Background

Tafazzin (TAZ), a transmembrane protein contributes in mitochondrial structural and functional modifications through cardiolipin remodeling. TAZ mutations are associated with several diseases, but studies on the role of TAZ protein in carcinogenesis and radiotherapy (RT) response is lacking. Therefore we investigated the TAZ expression in rectal cancer, and its correlation with RT, clinicopathological and biological variables in the patients participating in a clinical trial of preoperative RT.

Methods

140 rectal cancer patients were included in this study, of which 65 received RT before surgery and the rest underwent surgery alone. TAZ expression was determined by immunohistochemistry in primary cancer, distant, adjacent normal mucosa and lymph node metastasis. In-silico protein-protein interaction analysis was performed to study the predictive functional interaction of TAZ with other oncoproteins.

Results

TAZ showed stronger expression in primary cancer and lymph node metastasis compared to distant or adjacent normal mucosa in both non-RT and RT patients. Strong TAZ expression was significantly higher in stages I-III and non-mucinious cancer of non-RT patients. In RT patients, strong TAZ expression in biopsy was related to distant recurrence, independent of gender, age, stages and grade (p = 0.043, HR, 6.160, 95% CI, 1.063–35.704). In silico protein-protein interaction study demonstrated that TAZ was positively related to oncoproteins, Livin, MAC30 and FXYD-3.

Conclusions

Strong expression of TAZ protein seems to be related to rectal cancer development and RT response, it can be a predictive biomarker of distant recurrence in patients with preoperative RT.

Place, publisher, year, edition, pages
PLoS, 2014
National Category
Cancer and Oncology Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-107922 (URN)10.1371/journal.pone.0098317 (DOI)000336839400065 ()
Available from: 2014-06-23 Created: 2014-06-23 Last updated: 2018-01-11Bibliographically approved
Bastami, S., Norling, C., Trinks, C., Holmlund, B., Walz, T. M., Ahlner, J. & Uppugunduri, S. (2013). Inhibitory effect of opiates on LPS mediated release of TNF and IL-8. Acta Oncologica, 52(5), 1022-1033
Open this publication in new window or tab >>Inhibitory effect of opiates on LPS mediated release of TNF and IL-8
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2013 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 52, no 5, p. 1022-1033Article in journal (Refereed) Published
Abstract [en]

Most patients with advanced cancer experience severe pain and are often treated with opiates. Cancer patients are especially susceptible to opportunistic infections due to treatment with immunosuppressive and cytostatic drugs. Since opiates have been demonstrated to have immunomodulatory effects, it is of clinical importance to evaluate potential differences between commonly used opiates with regard to their effect on the immune system. The aim of this study was to evaluate the effect of morphine, tramadol, fentanyl and ketobemidone on the functioning of the immune system with special reference to TNF and IL-8 release. Method. U-937 cells were preincubated with different concentrations of opioids followed by stimulation with LPS 100 μg/ml for three hours. The effect of opioids on the levels of cytokine mRNA was studied using RT-PCR. Erk and Akt phosphorylation was also measured by Western blot. Results. All opioids with the exception of fentanyl were capable of inhibiting TNF release from U-937 cells. Morphine had no effect on IL-8 release but the effect of other opiates was almost the same as the effect on TNF. All opioids with the exception of fentanyl were capable of inhibiting production of mRNA for TNF and IL-8. The observed effects of opiates were not always reversible by naloxone, suggesting that the effects might be mediated by other receptors or through a non-receptor mediated direct effect. Although preliminary evidence suggests the involvement of Erk and Akt pathways, further studies are needed to unravel the intracellular pathways involved in mediating the effects of opiates. Our data suggests that the order of potency with regard to inhibition of cytokine release is as follows: tramadol > ketobemidone > morphine > fentanyl. Conclusion. Further studies are needed to understand the clinical implications of the observed immunosuppressive effects of tramadol and ketobemidone and to improve opioid treatment strategies in patients with cancer.

Place, publisher, year, edition, pages
Informa Healthcare, 2013
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-89960 (URN)10.3109/0284186X.2012.737932 (DOI)23145506 (PubMedID)
Available from: 2013-03-12 Created: 2013-03-12 Last updated: 2017-12-06
Olsson, H., Jansson, A., Holmlund, B. & Gunnarsson, C. (2013). Methods for evaluating HER2 status in breast cancer: comparison of IHC, FISH, and real-time PCR analysis of formalin-fixed paraffin-embedded tissue. Pathology and Laboratory Medicine International, 5, 31-37
Open this publication in new window or tab >>Methods for evaluating HER2 status in breast cancer: comparison of IHC, FISH, and real-time PCR analysis of formalin-fixed paraffin-embedded tissue
2013 (English)In: Pathology and Laboratory Medicine International, ISSN 1179-2698, Vol. 5, p. 31-37Article in journal (Refereed) Published
Abstract [en]

The human epidermal growth factor receptor 2 gene (HER2) is amplified in approximately 15%–20% of all breast cancers. This results in overexpression of the HER2 protein, which is associated with worse clinical outcomes in breast cancer patients. Several studies have shown that trastuzumab, a monoclonal antibody that interferes with the HER2/neu receptor, can improve overall survival in patients with HER2-positive breast cancer. Immunohistochemistry (IHC), combined with different methods for in situ hybridization, is currently used for routine assessment of HER2 status. The aim of the present study was to determine whether real-time polymerase chain reaction (PCR) can serve as a supplementary method for evaluation of HER2 status in primary breast cancer. For this purpose, 145 formalin-fixed paraffin-embedded primary breast cancer samples were tested by real-time PCR amplification of HER2, using amyloid precursor protein as a reference. The results were compared with HER2 status determined by fluorescence in situ hybridization (FISH) and IHC. The specificity, sensitivity, and reproducibility of real-time PCR were evaluated, and a comparison of formalin-fixed and fresh-frozen samples was performed. This showed concordance of 93% between real-time PCR and FISH, and 86% between real-time PCR and IHC. Therefore, we suggest that real-time PCR can be a useful supplementary method for assessment of HER2 status.

Place, publisher, year, edition, pages
Dove Medical Press, 2013
Keywords
17q, breast cancer, HER2, real-time PCR
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-105270 (URN)10.2147/PLMI.S44976 (DOI)
Available from: 2014-03-14 Created: 2014-03-14 Last updated: 2017-12-05Bibliographically approved
Holmqvist (Knutsen), A., Holmlund, B., Ardsby, M., Pathak, S. & Sun, X.-F. (2013). PINCH expression in relation to radiation response in co-cultured colon cancer cells and in rectal cancer patients. Oncology Reports, 30(5), 2097-2104
Open this publication in new window or tab >>PINCH expression in relation to radiation response in co-cultured colon cancer cells and in rectal cancer patients
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2013 (English)In: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 30, no 5, p. 2097-2104Article in journal (Refereed) Published
Abstract [en]

Particularly interesting new cysteine-histidine rich protein (PINCH), involved in cell spreading, motility and proliferation, has been shown to enhance radioresistance in colon cancer cell lines. The expression of PINCH in relation to radiation was studied in co-cultured colon cancer cells. Furthermore, the clinical significance between PINCH and radiotherapy (RT) was analyzed in rectal cancer patients with or without RT. The relative PINCH expression in colon cancer (KM12C) cells cultured separately and in co-culture was examined by western blotting and real-time PCR, and was analyzed over a period of 8 and 24 h after radiation. PINCH expression was immunohistochemically examined in 137 primary rectal tumors for which 65 cases did not receive RT and 72 cases received RT. PINCH expression tended to decrease from that in the separately cultured KM12C cells without radiation to that in cells with radiation at 8 h (P=0.060); while in the co-cultured cells, no significant difference was found (P=0.446). In patients with RT, strong PINCH expression was related to worse survival, when compared to patients with weak expression, independent of TNM stage, degree of differentiation, age and p53 status (P=0.029, RR 4.03, 95% CI 1.34-12.1). No survival relationship for the patients without RT was observed (P=0.287). A statistical interaction analysis between PINCH, RT and survival showed a trend towards significance (P=0.057). In conclusion, PINCH predicts survival in rectal cancer patients with RT, but not in patients without RT. The expression of PINCH may be regulated by radiation and by environmental factors surrounding the cells.

Place, publisher, year, edition, pages
Spandidos Publications, 2013
Keywords
co-culture, immunohistochemistry, PINCH, prognosis, radiation, rectal cancer
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-99392 (URN)10.3892/or.2013.2673 (DOI)000324540300012 ()
Note

Funding Agencies|Foundation of Oncological Clinical Research in Linkoping||Swedish Cancer Foundation||Swedish Research Council||Health Research Council in Southeast Sweden||

Available from: 2013-10-17 Created: 2013-10-17 Last updated: 2017-12-06Bibliographically approved
Holmqvist Knutsen, A., Gao, J.-F., Holmlund, B., Adell, G., Carstensen, J. & Sun, X.-F. (2012). PINCH is an independent prognostic factor in rectal cancer patients without preoperative radiotherapy: A study in a Swedish rectal cancer trial of preoperative radiotherapy. BMC Cancer, 12(65)
Open this publication in new window or tab >>PINCH is an independent prognostic factor in rectal cancer patients without preoperative radiotherapy: A study in a Swedish rectal cancer trial of preoperative radiotherapy
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2012 (English)In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 12, no 65Article in journal (Refereed) Published
Abstract [en]

Background and Purpose: The clinical significance between particularly interesting new cysteine-histidine rich protein (PINCH) expression and radiotherapy (RT) in tumours is not known. In this study, the expression of PINCH and its relationship to RT, clinical, pathological and biological factors were studied in rectal cancer patients.

Material and Methods: PINCH expression determined by immunohistochemistry was analysed at the invasive margin and inner tumour area in 137 primary rectal adenocarcinomas (72 cases without RT and 65 cases with RT). PINCH expression in colon fibroblast cell line (CCD-18 Co) was determined by Western blot.

Results: In patients without RT, strong PINCH expression at the invasive margin of primary tumours was related to worse survival, compared to patients with weak expression, independent of TNM stage and differentiation (p = 0.03). No survival relationship in patients with RT was observed (p = 0.64). Comparing the non-RT with RT subgroup, there was no difference in PINCH expression in primary tumours (invasive margin (p = 0.68)/inner tumour area (p = 0.49).

Conclusions: PINCH expression at the invasive margin was an independent prognostic factor in patients without RT. RT does not seem to directly affect the PINCH expression.

 

Place, publisher, year, edition, pages
BioMed Central, 2012
Keywords
PINCH, Radiotherapy, Prognosis, Rectal cancer, Immunohistochemistry
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-66104 (URN)10.1186/1471-2407-12-65 (DOI)000301425700001 ()
Note
funding agencies|Swedish Cancer Foundation||Swedish Research Council||Health Research Council in the South-East of Sweden||Available from: 2011-03-04 Created: 2011-03-03 Last updated: 2017-12-11Bibliographically approved
Perez-Tenorio, G., Karlsson, E., Ahnström, M., Olsson, B., Holmlund, B., Nordenskjöld, B., . . . Stål, O. (2011). Clinical potential of the mTOR targets S6K1 and S6K2 in breast cancer. Breast Cancer Research and Treatment, 128(3), 713-723
Open this publication in new window or tab >>Clinical potential of the mTOR targets S6K1 and S6K2 in breast cancer
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2011 (English)In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 128, no 3, p. 713-723Article in journal (Refereed) Published
Abstract [en]

The mammalian target of rapamycin (mTOR) and its substrates S6K1 and S6K2 regulate cell growth, proliferation, and metabolism through translational control. RPS6KB1 (S6K1) and RPS6KB2 (S6K2) are situated in the commonly amplified 17q21-23 and 11q13 regions. S6K1 amplification and protein overexpression have earlier been associated with a worse outcome in breast cancer, but information regarding S6K2 is scarce. The aim of this study was to evaluate the prognostic and treatment predictive relevance of S6K1/S6K2 gene amplification, as well as S6K2 protein expression in breast cancer. S6K1/S6K2 gene copy number was determined by real-time PCR in 207 stage II breast tumors and S6K2 protein expression was investigated by immunohistochemistry in 792 node-negative breast cancers. S6K1 amplification/gain was detected in 10.7%/21.4% and S6K2 amplification/gain in 4.3%/21.3% of the tumors. S6K2 protein was detected in the nucleus (38%) and cytoplasm (76%) of the tumor cells. S6K1 amplification was significantly associated with HER2 gene amplification and protein expression. S6K2 amplification correlated significantly with high S6K2 mRNA levels, ER+ status and CCND1 amplification. S6K1 and S6K2 gene amplification was associated with a worse prognosis independent of HER2 and CCND1. S6K2 gain and nuclear S6K2 expression was related to an improved benefit from tamoxifen among patients with ER+, respectively ER+/PgR+ tumors. In the ER+/PgR- subgroup, nuclear S6K2 rather indicated decreased tamoxifen responsiveness. S6K1 amplification predicted reduced benefit from radiotherapy. This is the first study showing that S6K2 amplification and overexpression, like S6K1 amplification, have prognostic and treatment predictive significance in breast cancer.

Place, publisher, year, edition, pages
Springer Science Business Media, 2011
Keywords
mTOR; S6 kinase; 17q21-23; 11q13; Gene amplification; Tamoxifen response
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-69784 (URN)10.1007/s10549-010-1058-x (DOI)000292557100013 ()
Note
The original publication is available at www.springerlink.com: Gizeh Perez-Tenorio, Elin Karlsson, Marie Ahnström, Birgit Olsson, Birgitta Holmlund, Bo Nordenskjöld, Tommy Fornander, Lambert Skoog and Olle Stål, Clinical potential of the mTOR targets S6K1 and S6K2 in breast cancer, 2011, Breast Cancer Research and Treatment, (128), 3, 713-723. http://dx.doi.org/10.1007/s10549-010-1058-x Copyright: Springer Science Business Media http://www.springerlink.com/Available from: 2011-08-10 Created: 2011-08-08 Last updated: 2017-12-08
Trinks, C., Severinsson, E. A., Holmlund, B., Gréen, A., Green, H., Jönsson, J.-I., . . . Walz, T. (2011). The pan-ErbB tyrosine kinase inhibitor canertinib induces caspase-mediated cell death in human T-cell leukemia (Jurkat) cells. Biochemical and Biophysical Research Communications - BBRC, 410(3), 422-427
Open this publication in new window or tab >>The pan-ErbB tyrosine kinase inhibitor canertinib induces caspase-mediated cell death in human T-cell leukemia (Jurkat) cells
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2011 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 410, no 3, p. 422-427Article in journal (Refereed) Published
Abstract [en]

Canertinib is a novel ErbB-receptor inhibitor currently in clinical development for the treatment of solid tumors overexpressing ErbB-receptors. We have recently demonstrated that canertinib displays anti-proliferative and pro-apoptotic effects in human myeloid leukemia cells devoid of ErbB-receptors. The mechanism mediating these effects are however unknown. In this study, we show that canertinib is able to act as a multi-kinase inhibitor by inhibition of several intracellular kinases involved in T-cell signaling such as Akt, Erk1/2 and Zap-70, and reduced Lck protein expression in the human T-cell leukemia cell line Jurkat. Treatment with canertinib at a concentration of 2 mu M caused accumulation of Jurkat cells in the G(1) cell cycle phase and increased doses induced apoptosis in a time-dependent manner. Apoptotic signs of treated cells were detected by Annexin V staining and cleavage of PARP, caspase-3, -8, -9, -10 and Bid. A subset of the pro-apoptotic signals mediated by canertinib could be significantly reduced by specific caspase inhibitors. Taken together, these results demonstrate the dual ability of canertinib to downregulate important signaling pathways and to activate caspase-mediated intrinsic apoptosis pathway in human T-cell leukemia cells.

Place, publisher, year, edition, pages
Elsevier Science B.V., Amsterdam, 2011
Keywords
T-cell leukemia; Canertinib; ErbB-receptor; Apoptosis; Caspase; Intracellular signaling
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-69797 (URN)10.1016/j.bbrc.2011.05.148 (DOI)000292797700009 ()
Available from: 2011-08-10 Created: 2011-08-08 Last updated: 2017-12-08
Pfeifer, D., Wallin, Å., Holmlund, B. & Sun, X.-F. (2009). Protein expression following gamma-irradiation relevant to growth arrest and apoptosis in colon cancer cells with mutant p53. Journal of Cancer Research and Clinical Oncology, 135(11), 1583-1592
Open this publication in new window or tab >>Protein expression following gamma-irradiation relevant to growth arrest and apoptosis in colon cancer cells with mutant p53
2009 (English)In: Journal of Cancer Research and Clinical Oncology, ISSN 0171-5216, E-ISSN 1432-1335, Vol. 135, no 11, p. 1583-1592Article in journal (Refereed) Published
Abstract [en]

We previously found that p53, p73, survivin and PRL were implicated in the outcome of radiotherapy in rectal cancer patients. In the present study, we tried to understand mechanisms of colon cancer cell line response to radiation based on protein expression related to proliferation and apoptosis. KM12C, KM12SM and KM12L4a, cell lines with one origin, were radiated with 0, 10 or 15 Gy γ-radiation. Radiosensitivity was determined with cell cycle and apoptosis analysis, and protein expression of TAp73, ΔNp73, mutated p53, survivin and PRL-3 was determined by Western blot. KM12C showed transient G2-arrest, low apoptosis and up-regulation of resistance factors such as PRL-3. In KM12C expression of ΔNp73 increased after 10Gy, but not after 15Gy. KM12SM had permanent G2-arrest, low apoptosis and showed up-regulation of the anti-apoptotic survivin and down-regulation of the pro-apoptotic TAp73 and the radioresistance factor PRL-3 was down-regulated. KM12L4a, the most radiosensitive cell line, showed up-regulation of TAp73 and down-regulation/no up-regulation of resistance factors such as ΔNp73, survivin and PRL-3 after radiation. In conclusion, the KM12C cell line was more radioresistant than KM12L4a regarding apoptosis and certain apoptotic proteins. The radiosensitivity of KM12L4a might partly depend on the lack of up-regulation of proteins negative for the outcome of radiotherapy.

 

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-14786 (URN)10.1007/s00432-009-0606-4 (DOI)
Available from: 2008-09-24 Created: 2008-09-24 Last updated: 2017-12-13Bibliographically approved
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