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      Potential Utility of Cell Free High Mobility Group AT-hook 2 ( HMGA2) as a Prognostic Biomarker in Liquid Biopsies of Oral Squamous Cell Carcinoma

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          Abstract

          Background:

          Locoregional spread is a frequent finding in oral cancer which dictates poor prognosis. HMGA2 expression has been linked to malignant traits of oral cancer in tissue biopsies however, data on HMGA2 expression in liquid biopsies in oral cancer is sparse. Purpose of this study was to explore prognostic relevance of HMGA2 in liquid biopsies of oral cancer patients.

          Patients and Methods:

          After obtaining approval from Institutional Review Board of Ziauddin University and informed written consent from study subjects, expression of circulating HMGA2 was evaluated in 96 OSCC cases and 100 age and sex matched controls via real time PCR using specific set of primers. We further analyzed relationship of various sociodemographic and clinicopathological variables with HMGA2expression and explored its prognostic potential.

          Results:

          Expression was seen in 22 (23%) cases. A higher expression was observed among subjects with local invasion (52.6% vs 47.4 %), distant metastasis (71.4% vs 28.6%) and tumor recurrence (57.1% vs 42.9%) p <0.05. Subjects having HMGA2 expression had a poor survival compared to HMGA2 negative (13.6% vs 35.4%), p <0.05.

          Conclusion:

          Circulating HMGA2 reflects presence of local invasion and distant metastasis and dictates poor prognosis in OSCC. It may contribute in categorizing high risk patients using a minimally invasive technique who are likely to benefit from targeted therapy.

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          Most cited references17

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          Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries

          This article provides a status report on the global burden of cancer worldwide using the GLOBOCAN 2018 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer, with a focus on geographic variability across 20 world regions. There will be an estimated 18.1 million new cancer cases (17.0 million excluding nonmelanoma skin cancer) and 9.6 million cancer deaths (9.5 million excluding nonmelanoma skin cancer) in 2018. In both sexes combined, lung cancer is the most commonly diagnosed cancer (11.6% of the total cases) and the leading cause of cancer death (18.4% of the total cancer deaths), closely followed by female breast cancer (11.6%), prostate cancer (7.1%), and colorectal cancer (6.1%) for incidence and colorectal cancer (9.2%), stomach cancer (8.2%), and liver cancer (8.2%) for mortality. Lung cancer is the most frequent cancer and the leading cause of cancer death among males, followed by prostate and colorectal cancer (for incidence) and liver and stomach cancer (for mortality). Among females, breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death, followed by colorectal and lung cancer (for incidence), and vice versa (for mortality); cervical cancer ranks fourth for both incidence and mortality. The most frequently diagnosed cancer and the leading cause of cancer death, however, substantially vary across countries and within each country depending on the degree of economic development and associated social and life style factors. It is noteworthy that high-quality cancer registry data, the basis for planning and implementing evidence-based cancer control programs, are not available in most low- and middle-income countries. The Global Initiative for Cancer Registry Development is an international partnership that supports better estimation, as well as the collection and use of local data, to prioritize and evaluate national cancer control efforts. CA: A Cancer Journal for Clinicians 2018;0:1-31. © 2018 American Cancer Society.
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            The tumor suppressor microRNA let-7 represses the HMGA2 oncogene.

            HMGA2, a high-mobility group protein, is oncogenic in a variety of tumors, including benign mesenchymal tumors and lung cancers. Knockdown of Dicer in HeLa cells revealed that the HMGA2 gene is transcriptionally active, but its mRNA is destabilized in the cytoplasm through the microRNA (miRNA) pathway. HMGA2 was derepressed upon inhibition of let-7 in cells with high levels of the miRNA. Ectopic expression of let-7 reduced HMGA2 and cell proliferation in a lung cancer cell. The effect of let-7 on HMGA2 was dependent on multiple target sites in the 3' untranslated region (UTR), and the growth-suppressive effect of let-7 on lung cancer cells was rescued by overexpression of the HMGA2 ORF without a 3'UTR. Our results provide a novel example of suppression of an oncogene by a tumor-suppressive miRNA and suggest that some tumors activate the oncogene through chromosomal translocations that eliminate the oncogene's 3'UTR with the let-7 target sites.
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              Disrupting the pairing between let-7 and Hmga2 enhances oncogenic transformation.

              MicroRNAs (miRNAs) are approximately 22-nucleotide RNAs that can pair to sites within messenger RNAs to specify posttranscriptional repression of these messages. Aberrant miRNA expression can contribute to tumorigenesis, but which of the many miRNA-target relationships are relevant to this process has been unclear. Here, we report that chromosomal translocations previously associated with human tumors disrupt repression of High Mobility Group A2 (Hmga2) by let-7 miRNA. This disrupted repression promotes anchorage-independent growth, a characteristic of oncogenic transformation. Thus, losing miRNA-directed repression of an oncogene provides a mechanism for tumorigenesis, and disrupting a single miRNA-target interaction can produce an observable phenotype in mammalian cells.
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                Author and article information

                Journal
                Asian Pac J Cancer Prev
                Asian Pac J Cancer Prev
                APJCP
                Asian Pacific Journal of Cancer Prevention : APJCP
                West Asia Organization for Cancer Prevention (Iran )
                1513-7368
                2476-762X
                February 2021
                : 22
                : 2
                : 407-412
                Affiliations
                [1 ] Ziauddin University, Pakistan.
                [2 ] Biochemsitry, Director Postgraduate Ziauddin University, Pakistan.
                [3 ] Karachi Institute of Radiotherapy and Nuclear Medicine, Pakistan.
                [4 ] Jinnah Sind Medical University, Pakistan.
                [5 ] Anatomy, King Saud Bin Abdul Aziz University, Saudi Arabia.
                [6 ] Internal, Medicine, Chinniot General Hospital, Pakistan.
                Author notes
                [* ]For Correspondence: nosheenrashid6@hotmail.com
                Article
                10.31557/APJCP.2021.22.2.407
                8190352
                33639654
                a611b830-f3bf-4175-9c86-f47274589c5a

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License, ( http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 7 September 2020
                : 5 February 2021
                Categories
                Research Article

                oscc,oral cancer,hmga2,liquid biopsy,plasma
                oscc, oral cancer, hmga2, liquid biopsy, plasma

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