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Association of anti-apoptotic Mcl-1L isoform expression with radioresistance of oral squamous carcinoma cells
Oral cancer is a common cancer and a major health problem in the Indian subcontinent. At our laboratory Mcl-1, an anti-apoptotic member of the Bcl-2 family has been demonstrated to be overexpressed in oral cancers and to predict outcome in oral cancer patients treated with definitive radiotherapy. T...
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| Published in: | Radiation oncology (London, England) England), 2012-08, Vol.7 (1), p.135-135, Article 135 |
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| creator | Palve, Vinayak C Teni, Tanuja R |
| description | Oral cancer is a common cancer and a major health problem in the Indian subcontinent. At our laboratory Mcl-1, an anti-apoptotic member of the Bcl-2 family has been demonstrated to be overexpressed in oral cancers and to predict outcome in oral cancer patients treated with definitive radiotherapy. To study the role of Mcl-1 isoforms in radiation response of oral squamous carcinoma cells (OSCC), we investigated in the present study, the association of Mcl-1 isoform expression with radiosensitivity of OSCC, using siRNA strategy.
The time course expression of Mcl-1 splice variants (Mcl-1L, Mcl-1S & Mcl-1ES) was studied by RT-PCR, western blotting & immunofluorescence, post-irradiation in oral cell lines [immortalized FBM (radiosensitive) and tongue cancer AW8507 & AW13516 (radioresistant)]of relatively differing radiosensitivities. The effect of Mcl-1L knockdown alone or in combination with ionizing radiation (IR) on cell proliferation, apoptosis & clonogenic survival, was investigated in AW8507 & AW13516 cells. Further the expression of Mcl-1L protein was assessed in radioresistant sublines generated by fractionated ionizing radiation (FIR).
Three to six fold higher expression of anti-apoptotic Mcl-1L versus pro-apoptotic Mcl-1S was observed at mRNA & protein levels in all cell lines, post-irradiation. Sustained high levels of Mcl-1L, downregulation of pro-apoptotic Bax & Bak and a significant (P |
| doi_str_mv | 10.1186/1748-717X-7-135 |
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The time course expression of Mcl-1 splice variants (Mcl-1L, Mcl-1S & Mcl-1ES) was studied by RT-PCR, western blotting & immunofluorescence, post-irradiation in oral cell lines [immortalized FBM (radiosensitive) and tongue cancer AW8507 & AW13516 (radioresistant)]of relatively differing radiosensitivities. The effect of Mcl-1L knockdown alone or in combination with ionizing radiation (IR) on cell proliferation, apoptosis & clonogenic survival, was investigated in AW8507 & AW13516 cells. Further the expression of Mcl-1L protein was assessed in radioresistant sublines generated by fractionated ionizing radiation (FIR).
Three to six fold higher expression of anti-apoptotic Mcl-1L versus pro-apoptotic Mcl-1S was observed at mRNA & protein levels in all cell lines, post-irradiation. Sustained high levels of Mcl-1L, downregulation of pro-apoptotic Bax & Bak and a significant (P < 0.05) reduction in apoptosis was observed in the more radioresistant AW8507, AW13516 versus FBM cells, post-IR. The ratios of anti to pro-apoptotic proteins were high in AW8507 as compared to FBM. Treatment with Mcl-1L siRNA alone or in combination with IR significantly (P < 0.01) increased apoptosis viz. 17.3% (IR), 25.3% (siRNA) and 46.3% (IR plus siRNA) and upregulated pro-apoptotic Bax levels in AW8507 cells. Combination of siRNA & IR treatment significantly (P < 0.05) reduced cell proliferation and clonogenic survival of radioresistant AW8507 & AW13516 cells, suggesting a synergistic effect of the Mcl-1L siRNA with IR on radiosensitivity. Interestingly, during the development of radioresistant sublines using FIR, high expression of Mcl-1L was observed.
Our studies suggest that Mcl-1L isoform has an important role in the survival and radioresistance of OSCC and may be a promising therapeutic target in oral cancers.]]></description><identifier>ISSN: 1748-717X</identifier><identifier>EISSN: 1748-717X</identifier><identifier>DOI: 10.1186/1748-717X-7-135</identifier><identifier>PMID: 22873792</identifier><language>eng</language><publisher>England: BioMed Central</publisher><subject>Alternative Splicing ; Apoptosis ; Apoptosis - radiation effects ; bcl-2-Associated X Protein - genetics ; bcl-2-Associated X Protein - metabolism ; bcl-X Protein - genetics ; bcl-X Protein - metabolism ; Biotechnology ; Blotting, Western ; Cancer ; Carcinoma, Squamous Cell - genetics ; Carcinoma, Squamous Cell - pathology ; Carcinoma, Squamous Cell - radiotherapy ; Cell culture ; Cell Proliferation - radiation effects ; Cobalt Radioisotopes - adverse effects ; Deoxyribonucleic acid ; DNA ; Flow Cytometry ; Fluorescent Antibody Technique ; Humans ; Mouth Neoplasms - genetics ; Mouth Neoplasms - pathology ; Mouth Neoplasms - radiotherapy ; Myeloid Cell Leukemia Sequence 1 Protein ; Oral cancer ; Protein Isoforms ; Proteins ; Proto-Oncogene Proteins c-bcl-2 - genetics ; Proto-Oncogene Proteins c-bcl-2 - metabolism ; Proto-Oncogene Proteins c-bcl-2 - physiology ; Radiation therapy ; Radiation Tolerance - physiology ; Radiation, Ionizing ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; RNA, Messenger - genetics ; RNA, Small Interfering - genetics ; Studies ; Tumor Cells, Cultured ; Tumor Stem Cell Assay ; Tumors</subject><ispartof>Radiation oncology (London, England), 2012-08, Vol.7 (1), p.135-135, Article 135</ispartof><rights>2012 Palve and Teni; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</rights><rights>Copyright ©2012 Palve and Teni; licensee BioMed Central Ltd. 2012 Palve and Teni; licensee BioMed Central Ltd.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-b546t-5ed0f759e985135d02f2f72810ecad5145e70e630e769367a74ae36415350d883</citedby><cites>FETCH-LOGICAL-b546t-5ed0f759e985135d02f2f72810ecad5145e70e630e769367a74ae36415350d883</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3487741/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/1124996778?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,25730,27900,27901,36988,44565,53765,53767</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22873792$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Palve, Vinayak C</creatorcontrib><creatorcontrib>Teni, Tanuja R</creatorcontrib><title>Association of anti-apoptotic Mcl-1L isoform expression with radioresistance of oral squamous carcinoma cells</title><title>Radiation oncology (London, England)</title><addtitle>Radiat Oncol</addtitle><description><![CDATA[Oral cancer is a common cancer and a major health problem in the Indian subcontinent. At our laboratory Mcl-1, an anti-apoptotic member of the Bcl-2 family has been demonstrated to be overexpressed in oral cancers and to predict outcome in oral cancer patients treated with definitive radiotherapy. To study the role of Mcl-1 isoforms in radiation response of oral squamous carcinoma cells (OSCC), we investigated in the present study, the association of Mcl-1 isoform expression with radiosensitivity of OSCC, using siRNA strategy.
The time course expression of Mcl-1 splice variants (Mcl-1L, Mcl-1S & Mcl-1ES) was studied by RT-PCR, western blotting & immunofluorescence, post-irradiation in oral cell lines [immortalized FBM (radiosensitive) and tongue cancer AW8507 & AW13516 (radioresistant)]of relatively differing radiosensitivities. The effect of Mcl-1L knockdown alone or in combination with ionizing radiation (IR) on cell proliferation, apoptosis & clonogenic survival, was investigated in AW8507 & AW13516 cells. Further the expression of Mcl-1L protein was assessed in radioresistant sublines generated by fractionated ionizing radiation (FIR).
Three to six fold higher expression of anti-apoptotic Mcl-1L versus pro-apoptotic Mcl-1S was observed at mRNA & protein levels in all cell lines, post-irradiation. Sustained high levels of Mcl-1L, downregulation of pro-apoptotic Bax & Bak and a significant (P < 0.05) reduction in apoptosis was observed in the more radioresistant AW8507, AW13516 versus FBM cells, post-IR. The ratios of anti to pro-apoptotic proteins were high in AW8507 as compared to FBM. Treatment with Mcl-1L siRNA alone or in combination with IR significantly (P < 0.01) increased apoptosis viz. 17.3% (IR), 25.3% (siRNA) and 46.3% (IR plus siRNA) and upregulated pro-apoptotic Bax levels in AW8507 cells. Combination of siRNA & IR treatment significantly (P < 0.05) reduced cell proliferation and clonogenic survival of radioresistant AW8507 & AW13516 cells, suggesting a synergistic effect of the Mcl-1L siRNA with IR on radiosensitivity. Interestingly, during the development of radioresistant sublines using FIR, high expression of Mcl-1L was observed.
Our studies suggest that Mcl-1L isoform has an important role in the survival and radioresistance of OSCC and may be a promising therapeutic target in oral cancers.]]></description><subject>Alternative Splicing</subject><subject>Apoptosis</subject><subject>Apoptosis - radiation effects</subject><subject>bcl-2-Associated X Protein - genetics</subject><subject>bcl-2-Associated X Protein - metabolism</subject><subject>bcl-X Protein - genetics</subject><subject>bcl-X Protein - metabolism</subject><subject>Biotechnology</subject><subject>Blotting, Western</subject><subject>Cancer</subject><subject>Carcinoma, Squamous Cell - genetics</subject><subject>Carcinoma, Squamous Cell - pathology</subject><subject>Carcinoma, Squamous Cell - radiotherapy</subject><subject>Cell culture</subject><subject>Cell Proliferation - radiation effects</subject><subject>Cobalt Radioisotopes - adverse effects</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>Flow Cytometry</subject><subject>Fluorescent Antibody Technique</subject><subject>Humans</subject><subject>Mouth Neoplasms - genetics</subject><subject>Mouth Neoplasms - pathology</subject><subject>Mouth Neoplasms - radiotherapy</subject><subject>Myeloid Cell Leukemia Sequence 1 Protein</subject><subject>Oral cancer</subject><subject>Protein Isoforms</subject><subject>Proteins</subject><subject>Proto-Oncogene Proteins c-bcl-2 - genetics</subject><subject>Proto-Oncogene Proteins c-bcl-2 - metabolism</subject><subject>Proto-Oncogene Proteins c-bcl-2 - physiology</subject><subject>Radiation therapy</subject><subject>Radiation Tolerance - physiology</subject><subject>Radiation, Ionizing</subject><subject>Real-Time Polymerase Chain Reaction</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>RNA, Messenger - genetics</subject><subject>RNA, Small Interfering - genetics</subject><subject>Studies</subject><subject>Tumor Cells, Cultured</subject><subject>Tumor Stem Cell Assay</subject><subject>Tumors</subject><issn>1748-717X</issn><issn>1748-717X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>PIMPY</sourceid><sourceid>DOA</sourceid><recordid>eNp1ks1v1DAQxSMEoqVw5oYicQ61YztjX5BKxUelRVxA4mbNOk7rVZJJ7aTAf4_DllVXgpOtN08_-81MUbzk7A3nujnnIHUFHL5XUHGhHhWnB-Xxg_tJ8SylHWNSCWaeFid1rUGAqU-L4SIlcgHnQGNJXYnjHCqcaJppDq787PqKb8qQqKM4lP7nFH1Kq_dHmG_KiG2grIQ04-j8CqCIfZluFxxoSaXD6MJIA5bO9316XjzpsE_-xf15Vnz78P7r5adq8-Xj1eXFptoq2cyV8i3rQBlvtMqpWlZ3dQe15sw7bBWXygPzjWAeGiMaQJDoRSO5Eoq1Wouz4mrPbQl3dophwPjLEgb7R6B4bTHmfL23yqvWcLNVyijZecRaaQNKM2hkw5TMrLd71rRsB986P8454hH0uDKGG3tNd1ZIDSB5BrzbA7aB_gM4rjga7Do6u47Ogs0tyJDX97-IdLv4NNsdLXHMTbSc19KYBmDNfb53uUgpRd8dXuHMrgvzD-6rh-kO_r8bIn4DoQu9Ng</recordid><startdate>20120808</startdate><enddate>20120808</enddate><creator>Palve, Vinayak C</creator><creator>Teni, Tanuja R</creator><general>BioMed Central</general><general>BioMed Central Ltd</general><general>BMC</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QO</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FD</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>P64</scope><scope>PHGZM</scope><scope>PHGZT</scope><scope>PIMPY</scope><scope>PJZUB</scope><scope>PKEHL</scope><scope>PPXIY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20120808</creationdate><title>Association of anti-apoptotic Mcl-1L isoform expression with radioresistance of oral squamous carcinoma cells</title><author>Palve, Vinayak C ; Teni, Tanuja R</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-b546t-5ed0f759e985135d02f2f72810ecad5145e70e630e769367a74ae36415350d883</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Alternative Splicing</topic><topic>Apoptosis</topic><topic>Apoptosis - radiation effects</topic><topic>bcl-2-Associated X Protein - genetics</topic><topic>bcl-2-Associated X Protein - metabolism</topic><topic>bcl-X Protein - genetics</topic><topic>bcl-X Protein - metabolism</topic><topic>Biotechnology</topic><topic>Blotting, Western</topic><topic>Cancer</topic><topic>Carcinoma, Squamous Cell - genetics</topic><topic>Carcinoma, Squamous Cell - pathology</topic><topic>Carcinoma, Squamous Cell - radiotherapy</topic><topic>Cell culture</topic><topic>Cell Proliferation - radiation effects</topic><topic>Cobalt Radioisotopes - adverse effects</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>Flow Cytometry</topic><topic>Fluorescent Antibody Technique</topic><topic>Humans</topic><topic>Mouth Neoplasms - genetics</topic><topic>Mouth Neoplasms - pathology</topic><topic>Mouth Neoplasms - radiotherapy</topic><topic>Myeloid Cell Leukemia Sequence 1 Protein</topic><topic>Oral cancer</topic><topic>Protein Isoforms</topic><topic>Proteins</topic><topic>Proto-Oncogene Proteins c-bcl-2 - genetics</topic><topic>Proto-Oncogene Proteins c-bcl-2 - metabolism</topic><topic>Proto-Oncogene Proteins c-bcl-2 - physiology</topic><topic>Radiation therapy</topic><topic>Radiation Tolerance - physiology</topic><topic>Radiation, Ionizing</topic><topic>Real-Time Polymerase Chain Reaction</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>RNA, Messenger - genetics</topic><topic>RNA, Small Interfering - genetics</topic><topic>Studies</topic><topic>Tumor Cells, Cultured</topic><topic>Tumor Stem Cell Assay</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Palve, Vinayak C</creatorcontrib><creatorcontrib>Teni, Tanuja R</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Biotechnology Research Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Technology Research Database</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest Central (New)</collection><collection>ProQuest One Academic (New)</collection><collection>Publicly Available Content (ProQuest)</collection><collection>ProQuest Health & Medical Research Collection</collection><collection>ProQuest One Academic Middle East (New)</collection><collection>ProQuest One Health & Nursing</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>PubMed Central (Full Participant titles)</collection><collection>Directory of Open Access Journals</collection><jtitle>Radiation oncology (London, England)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Palve, Vinayak C</au><au>Teni, Tanuja R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Association of anti-apoptotic Mcl-1L isoform expression with radioresistance of oral squamous carcinoma cells</atitle><jtitle>Radiation oncology (London, England)</jtitle><addtitle>Radiat Oncol</addtitle><date>2012-08-08</date><risdate>2012</risdate><volume>7</volume><issue>1</issue><spage>135</spage><epage>135</epage><pages>135-135</pages><artnum>135</artnum><issn>1748-717X</issn><eissn>1748-717X</eissn><abstract><![CDATA[Oral cancer is a common cancer and a major health problem in the Indian subcontinent. At our laboratory Mcl-1, an anti-apoptotic member of the Bcl-2 family has been demonstrated to be overexpressed in oral cancers and to predict outcome in oral cancer patients treated with definitive radiotherapy. To study the role of Mcl-1 isoforms in radiation response of oral squamous carcinoma cells (OSCC), we investigated in the present study, the association of Mcl-1 isoform expression with radiosensitivity of OSCC, using siRNA strategy.
The time course expression of Mcl-1 splice variants (Mcl-1L, Mcl-1S & Mcl-1ES) was studied by RT-PCR, western blotting & immunofluorescence, post-irradiation in oral cell lines [immortalized FBM (radiosensitive) and tongue cancer AW8507 & AW13516 (radioresistant)]of relatively differing radiosensitivities. The effect of Mcl-1L knockdown alone or in combination with ionizing radiation (IR) on cell proliferation, apoptosis & clonogenic survival, was investigated in AW8507 & AW13516 cells. Further the expression of Mcl-1L protein was assessed in radioresistant sublines generated by fractionated ionizing radiation (FIR).
Three to six fold higher expression of anti-apoptotic Mcl-1L versus pro-apoptotic Mcl-1S was observed at mRNA & protein levels in all cell lines, post-irradiation. Sustained high levels of Mcl-1L, downregulation of pro-apoptotic Bax & Bak and a significant (P < 0.05) reduction in apoptosis was observed in the more radioresistant AW8507, AW13516 versus FBM cells, post-IR. The ratios of anti to pro-apoptotic proteins were high in AW8507 as compared to FBM. Treatment with Mcl-1L siRNA alone or in combination with IR significantly (P < 0.01) increased apoptosis viz. 17.3% (IR), 25.3% (siRNA) and 46.3% (IR plus siRNA) and upregulated pro-apoptotic Bax levels in AW8507 cells. Combination of siRNA & IR treatment significantly (P < 0.05) reduced cell proliferation and clonogenic survival of radioresistant AW8507 & AW13516 cells, suggesting a synergistic effect of the Mcl-1L siRNA with IR on radiosensitivity. Interestingly, during the development of radioresistant sublines using FIR, high expression of Mcl-1L was observed.
Our studies suggest that Mcl-1L isoform has an important role in the survival and radioresistance of OSCC and may be a promising therapeutic target in oral cancers.]]></abstract><cop>England</cop><pub>BioMed Central</pub><pmid>22873792</pmid><doi>10.1186/1748-717X-7-135</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Radiation oncology (London, England), 2012-08, Vol.7 (1), p.135-135, Article 135 |
| issn | 1748-717X 1748-717X |
| language | eng |
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| source | Publicly Available Content (ProQuest); PubMed Central |
| subjects | Alternative Splicing Apoptosis Apoptosis - radiation effects bcl-2-Associated X Protein - genetics bcl-2-Associated X Protein - metabolism bcl-X Protein - genetics bcl-X Protein - metabolism Biotechnology Blotting, Western Cancer Carcinoma, Squamous Cell - genetics Carcinoma, Squamous Cell - pathology Carcinoma, Squamous Cell - radiotherapy Cell culture Cell Proliferation - radiation effects Cobalt Radioisotopes - adverse effects Deoxyribonucleic acid DNA Flow Cytometry Fluorescent Antibody Technique Humans Mouth Neoplasms - genetics Mouth Neoplasms - pathology Mouth Neoplasms - radiotherapy Myeloid Cell Leukemia Sequence 1 Protein Oral cancer Protein Isoforms Proteins Proto-Oncogene Proteins c-bcl-2 - genetics Proto-Oncogene Proteins c-bcl-2 - metabolism Proto-Oncogene Proteins c-bcl-2 - physiology Radiation therapy Radiation Tolerance - physiology Radiation, Ionizing Real-Time Polymerase Chain Reaction Reverse Transcriptase Polymerase Chain Reaction RNA, Messenger - genetics RNA, Small Interfering - genetics Studies Tumor Cells, Cultured Tumor Stem Cell Assay Tumors |
| title | Association of anti-apoptotic Mcl-1L isoform expression with radioresistance of oral squamous carcinoma cells |
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